VCV000005294.120 - ClinVar

NM_001048174.2(MUTYH):c.1103G>A (p.Gly368Asp)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(73)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001048174.2(MUTYH):c.1103G>A (p.Gly368Asp)

Variation ID: 5294 Accession: VCV000005294.120

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p34.1 1: 45331556 (GRCh38) [ NCBI UCSC ] 1: 45797228 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 12, 2013	Nov 17, 2024	Aug 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001048174.2:c.1103G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001041639.1:p.Gly368Asp	missense
NM_001128425.2:c.1187G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001121897.1:p.Gly396Asp	missense
NM_001048171.2:c.1103G>A	NP_001041636.2:p.Gly368Asp	missense
NM_001048172.2:c.1106G>A	NP_001041637.1:p.Gly369Asp	missense
NM_001048173.2:c.1103G>A	NP_001041638.1:p.Gly368Asp	missense
NM_001048174.1:c.1103G>A
NM_001293190.2:c.1148G>A	NP_001280119.1:p.Gly383Asp	missense
NM_001293191.2:c.1136G>A	NP_001280120.1:p.Gly379Asp	missense
NM_001293192.2:c.827G>A	NP_001280121.1:p.Gly276Asp	missense
NM_001293195.2:c.1103G>A	NP_001280124.1:p.Gly368Asp	missense
NM_001293196.2:c.827G>A	NP_001280125.1:p.Gly276Asp	missense
NM_001350650.2:c.758G>A	NP_001337579.1:p.Gly253Asp	missense
NM_001350651.2:c.758G>A	NP_001337580.1:p.Gly253Asp	missense
NM_012222.3:c.1178G>A	NP_036354.1:p.Gly393Asp	missense
NR_146882.2:n.1331G>A		non-coding transcript variant
NR_146883.2:n.1180G>A		non-coding transcript variant
NC_000001.11:g.45331556C>T
NC_000001.10:g.45797228C>T
NG_008189.1:g.13915G>A
LRG_220:g.13915G>A
LRG_220t1:c.[1187G>A]

... more HGVS ... less HGVS

Protein change

G382D, G396D, G276D, G393D, G369D, G368D, G383D, G253D, G379D

Other names

p.G382D:GGT>GAT

Canonical SPDI

NC_000001.11:45331555:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00240 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.00240

Exome Aggregation Consortium (ExAC) 0.00280

The Genome Aggregation Database (gnomAD), exomes 0.00303

1000 Genomes Project 30x 0.00312

The Genome Aggregation Database (gnomAD) 0.00341

Trans-Omics for Precision Medicine (TOPMed) 0.00371

Links

dbSNP: rs36053993 ClinGen: CA011561 OMIM: 604933.0002 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MUTYH		-	-	GRCh38 GRCh37	2689	2845

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Endometrial cancer	Pathogenic (1)	no assertion criteria provided	Sep 1, 2011	RCV000005615.12
Familial adenomatous polyposis 2	Pathogenic/Likely pathogenic (32)	criteria provided, multiple submitters, no conflicts	Apr 2, 2024	RCV000005614.75
not provided	Pathogenic (19)	criteria provided, multiple submitters, no conflicts	Aug 1, 2024	RCV000079501.76
Hereditary cancer-predisposing syndrome	Pathogenic/Likely pathogenic (8)	criteria provided, multiple submitters, no conflicts	Dec 18, 2023	RCV000115748.35
not specified	not provided (1)	no classification provided	Sep 19, 2013	RCV000121598.12
Carcinoma of colon	Pathogenic (2)	no assertion criteria provided	Jul 24, 2014	RCV000144637.11
Familial adenomatous polyposis 2 Neoplasm of stomach	Pathogenic (1)	no assertion criteria provided	Jun 4, 2015	RCV000477907.11
Colorectal adenomatous polyposis, autosomal recessive, with pilomatricomas	Pathogenic (1)	criteria provided, single submitter	Aug 26, 2016	RCV000501239.13
Small intestine carcinoid	Likely pathogenic (1)	no assertion criteria provided	Mar 9, 2017	RCV000493920.9
Familial adenomatous polyposis 2 Neoplasm of stomach Pilomatrixoma	Pathogenic (1)	criteria provided, single submitter	May 18, 2017	RCV000515320.10
Ovarian carcinoma	Pathogenic (1)	criteria provided, single submitter	Jan 1, 2019	RCV001262769.9
Colon cancer	Pathogenic (1)	no assertion criteria provided	Aug 23, 2021	RCV001580144.9
Breast carcinoma	Pathogenic (1)	no assertion criteria provided	Aug 20, 2021	RCV001574076.9
Familial colorectal cancer	Pathogenic (1)	criteria provided, single submitter	Mar 25, 2022	RCV002051775.10
MUTYH-related disorder	Pathogenic (1)	no assertion criteria provided	Sep 10, 2024	RCV004528084.3
Diffuse midline glioma, H3 K27-altered	Pathogenic (1)	criteria provided, single submitter	Jul 26, 2023	RCV004785246.1
click to load more click to collapse

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Dec 21, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Vantari Genetics Accession: SCV000267061.1 First in ClinVar: Apr 13, 2016 Last updated: Apr 13, 2016
Pathogenic (Aug 26, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Colorectal adenomatous polyposis, autosomal recessive, with pilomatricomas Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000595873.1 First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017
Pathogenic (May 18, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pilomatrixoma Familial adenomatous polyposis 2 Gastric cancer Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000611285.1 First in ClinVar: Nov 11, 2017 Last updated: Nov 11, 2017
Pathogenic (Feb 27, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000111383.8 First in ClinVar: Jan 22, 2014 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MUTYH Number of individuals with the variant: 23 Sex: mixed
Pathogenic (Dec 18, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Familial adenomatous polyposis 2 (Autosomal dominant inheritance) Affected status: unknown Allele origin: unknown	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology Accession: SCV000993433.2 First in ClinVar: Sep 22, 2019 Last updated: Dec 31, 2019	Observation 1: Number of individuals with the variant: 1 Observation 2: Number of individuals with the variant: 1 Observation 3: Number of individuals with the variant: 1
Likely pathogenic (Jan 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: yes Allele origin: germline	GeneKor MSA Accession: SCV000821744.2 First in ClinVar: Oct 10, 2018 Last updated: Apr 24, 2020	Comment: This sequence change replaces Glycine with Aspartic acid at codon 396 of the MUTYH protein. The glycine residue is highly conserved in the Nudix Hydrolase … (more) This sequence change replaces Glycine with Aspartic acid at codon 396 of the MUTYH protein. The glycine residue is highly conserved in the Nudix Hydrolase domain of the protein and there is a moderate physiochemical difference between glycine and aspartic acid (Grantham Score 94).This variant is present in population databases (rs36053993, 0.4%) and has been reported in the literature. This variant has been reported to co-segregate with disease in patients affected with colorectal cancer, familial adenomatous polyposis (FAP), and attenuated FAP (PMID: 31159747, 19793053, 11818965 ) when found in the homozygous state or in compound heterozygosis with another MUTYH pathogenic variant. This variant is also known as c.1145G>A (p.Gly382Asp) in the literature. Experimental studies have shown that this missense change disrupts MUTYH protein function (PMID: 20848659 ; 15987719). The mutation databaseClinVar contains entries for this variant (Variation ID:5294). (less)
Pathogenic (May 26, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Familial adenomatous polyposis 2 Affected status: unknown Allele origin: unknown	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology Study: AGHI_GT Accession: SCV001423820.1 First in ClinVar: Jul 27, 2020 Last updated: Jul 27, 2020	Number of individuals with the variant: 1
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447077.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Primary dilated cardiomyopathy (present) Sex: female
Pathogenic (Jan 04, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001449666.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Number of individuals with the variant: 15
Pathogenic (Aug 13, 2021)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Familial adenomatous polyposis 2 Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000697670.2 First in ClinVar: Mar 17, 2018 Last updated: Sep 08, 2021	Publications: PubMed (7) PubMed: 22703879‚ 24278394‚ 25820570‚ 24953332‚ 20848659‚ 19836313‚ 27829682 Comment: Variant summary: MUTYH c.1187G>A (p.Gly396Asp) results in a non-conservative amino acid change located in the NUDIX hydrolase domain (IPR000086) of the encoded protein sequence. Five … (more) Variant summary: MUTYH c.1187G>A (p.Gly396Asp) results in a non-conservative amino acid change located in the NUDIX hydrolase domain (IPR000086) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.003 in 250814 control chromosomes in the gnomAD database, including 3 homozygotes. c.1187G>A has been reported in the literature in multiple individuals affected with MUTYH-Associated Polyposis (example: Castillejo_2014, DeLellis_2013, Ricci_2016). These data indicate that the variant is very likely to be associated with disease. Functional studies support a damaging outcome, and at least 2 independent labs have down reduced DNA glycosylase activity and a reduced ability to suppress the mutation frequency in a complementation assay (example: Goto_2010, Komine_2015, Kundu_2009). 32 ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Jun 04, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002501474.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (17) PubMed: 11818965‚ 22744763‚ 30676620‚ 18534194‚ 23361220‚ 31263571‚ 28687356‚ 24728327‚ 30306255‚ 30067863‚ 30333958‚ 29978187‚ 30322717‚ 30609409‚ 23805267‚ 27014339‚ 20418187 Number of individuals with the variant: 1 Secondary finding: no
Pathogenic (Dec 20, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002532208.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The MUTYH c.1187G>A (p.G396D) variant is a well-known pathogenic variant associated with autosomal recessive MUTYH-associated polyposis. This variant, also known as c.1145G>A (p.Gly382Asp), was observed … (more) The MUTYH c.1187G>A (p.G396D) variant is a well-known pathogenic variant associated with autosomal recessive MUTYH-associated polyposis. This variant, also known as c.1145G>A (p.Gly382Asp), was observed in 628/128314 (0.49%) chromosomes in the European (non-Finnish) population, with 3 homozygotes, in the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). It has been reported as homozygous or compound heterozygous with other pathogenic MUTYH variants in multiple individuals with colorectal cancer and polyposis (PMID: 11818965, 16557584, 16492921, 19394335, 21063410). In addition, this variant has been reported to co-segregate with disease in several families (PMID: 11818965, 16557584, 19793053). Functional studies have shown that this variant alters MUTYH protein function (PMID: 18534194, 20848659, 15987719, 12917422). Monoallelic carriers of this variant have shown a slightly increased risk for colorectal cancer (PMID: 21063410, 24444654). The variant has been reported in ClinVar (Variation ID 5294). Based on the current evidence available, this variant is interpreted as pathogenic. (less)	Publications: PubMed (11) PubMed: 11818965‚ 16557584‚ 16492921‚ 19394335‚ 21063410‚ 19793053‚ 18534194‚ 20848659‚ 15987719‚ 12917422‚ 24444654
Pathogenic (Aug 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial adenomatous polyposis 2 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002580176.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PM3_VSTR, PS4, PP1_STR, PS3_SUP, PP3	Number of individuals with the variant: 21 Sex: female
Pathogenic (Jul 02, 2018)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	MYH-associated polyposis Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV000837751.2 First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022
Pathogenic (Nov 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002011071.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023
Pathogenic (Apr 19, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial adenomatous polyposis 2 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV004175688.1 First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023
Pathogenic (Sep 14, 2020)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000601628.5 First in ClinVar: Dec 06, 2016 Last updated: Jan 06, 2024	Publications: PubMed (89): PubMed: 25186627 26556299 26681312 27153395 27829682 27870730 28127763 28152038 28195393 28503720 28577310 28634180 28687356 28709830 29371908 29785153 29978187 30067863 30256826 30291343 30306255 30309722 30322717 30333958 30582135 30609409 30620386 30676620 30702970 30833417 30877237 31159747 31263571 31285513 31447099 31512090 31618753 31980526 32088803 32231684 32338768 32570879 32830346 32854451 33087929 33258288 33384714 33442023 33504652 34259353 34308366 34347074 34426522 28135145 29766397 30604180 28944238 11818965 22744763 18534194 23361220 24728327 23805267 27014339 20418187 24082139 20848659 19998059 22703879 23625202 25820570 19836313 19953527 21178863 19032956 26332594 26822237 22473953 22926731 21952991 23108399 21063410 19732775 26202870 22158503 20618354 24444654 19394335 19620482 Comment: The MUTYH c.1187G>A (p.Gly396Asp) variant (also known as G396D and G382D) has been reported in the published literature in multiple cases of MUTYH-Associated Polyposis (MAP). … (more) The MUTYH c.1187G>A (p.Gly396Asp) variant (also known as G396D and G382D) has been reported in the published literature in multiple cases of MUTYH-Associated Polyposis (MAP). This variant is one of two pathogenic variants associated with at least 90% of cases of MAP in patients of European ancestry (PMIDs: 19032956 (2009), 22744763 (2012), 23361220 (2014), 28135145 (2017), 28944238 (2017), 29766397 (2018), 30604180 (2019)). Furthermore, this variant has been described to have a damaging effect on DNA binding and DNA glycosylase activity of the MUTYH protein (PMIDs: 18534194 (2008), 19032956 (2009), 19953527 (2010), 20418187 (2010), 25820570 (2015)). Based on the available information, this variant is classified as pathogenic. (less)
Pathogenic (Jul 19, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial adenomatous polyposis 2 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002017639.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial adenomatous polyposis 2 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000166443.14 First in ClinVar: Jun 15, 2014 Last updated: Feb 20, 2024	Publications: PubMed (15) PubMed: 28492532‚ 23035301‚ 11818965‚ 16557584‚ 17489848‚ 19793053‚ 16492921‚ 19394335‚ 21171015‚ 24444654‚ 15931596‚ 15987719‚ 18534194‚ 20848659‚ 23108399 Comment: This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 396 of the MUTYH protein … (more) This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 396 of the MUTYH protein (p.Gly396Asp). This variant is present in population databases (rs36053993, gnomAD 0.5%), including at least one homozygous and/or hemizygous individual. This variant is a known common cause of MUTYH-associated polyposis (PMID: 23035301). This variant has been reported to co-segregate with disease in individuals affected with colorectal cancer and polyposis (with polyp numbers ranging from 10 to >100) (PMID: 11818965, 16557584, 17489848, 19793053). MUTYH-related conditions are inherited in an autosomal recessive fashion. However, there is evidence that monoallelic pathogenic MUTYH variants including this particular variant are associated with increased risk of colon cancer (PMID: 16492921, 19394335, 21171015, 24444654, 15931596). This variant is also known as c.1145G>A (p.Gly382Asp). ClinVar contains an entry for this variant (Variation ID: 5294). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MUTYH function (PMID: 15987719, 18534194, 20848659, 23108399). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 26, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial adenomatous polyposis 2 Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004806971.1 First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024
Pathogenic (Feb 05, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial adenomatous polyposis 2 (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004836151.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (23) PubMed: 11818965‚ 12606733‚ 15036665‚ 15635083‚ 15987719‚ 16557584‚ 17489848‚ 18534194‚ 19032956‚ 19793053‚ 20418187‚ 20848659‚ 22473953‚ 22926731‚ 23108399‚ 23361220‚ 25590978‚ 25820570‚ 26202870‚ 27783336‚ 28135145‚ 29147111‚ 31159747 Comment: The c.1187G>A (p.Gly396Asp) variant in the MUTYH gene is located on the exon 13 and is predicted to replace glycine with aspartic acid at codon … (more) The c.1187G>A (p.Gly396Asp) variant in the MUTYH gene is located on the exon 13 and is predicted to replace glycine with aspartic acid at codon 396 of the MUTYH protein. This variant has been observed in homozygous or compound heterozygous state in multiple individuals with MUTYH-associated polyposis and colorectal cancer (PMID: 11818965, 12606733, 15635083, 16557584, 19032956, 23108399, 23361220, 25590978, 26202870, 27783336, 28135145, 29147111). This variant has been reported to co-segregate with disease in multiple individuals (PMID: 11818965, 16557584, 17489848, 19793053, 31159747). Experimental studies have shown that this variant affects MUTYH function and leads to a reduction in DNA binding and glycosylase activity (PMID: 11818965, 15036665, 15987719, 18534194, 20418187, 20848659, 22473953, 22926731, 23108399, 25820570). This missense change has been identified in 860/281146 chromosomes in the general population by the Genome Aggregation Database (gnomAD), including three homozygotes. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (REVEL score = 0.954). Based on these evidence, the c.1187G>A (p.Gly396Asp) variant in the MUTYH gene is classified as pathogenic. (less) Number of individuals with the variant: 998
Pathogenic (Apr 02, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial adenomatous polyposis 2 (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000245638.3 First in ClinVar: Sep 14, 2015 Last updated: Apr 20, 2024	Publications: PubMed (9) PubMed: 11818965‚ 23361220‚ 21178863‚ 22926731‚ 19032956‚ 19732775‚ 19836313‚ 18534194‚ 20848659 Comment: The p.Gly396Asp variant in MUTYH is a well-established pathogenic variant for MUTYH-related attenuated familial adenomatous polyposis and is estimated to account for 50-82% of MUTYH-associated … (more) The p.Gly396Asp variant in MUTYH is a well-established pathogenic variant for MUTYH-related attenuated familial adenomatous polyposis and is estimated to account for 50-82% of MUTYH-associated polyposis in European patients (Al-Tassan 2002 PMID: 11818965, Nielsen 2009 PMID: 17489848, Vogt 2009 PMID: 19732775, Nascimbeni 2010 PMID: 21178863, Aretz 2014 PMID: 23361220, ClinVar: Variation ID 5294). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 5294) and has been identified in 0.5% (367/68040) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2); however, this frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the p.Gly396Asp variant may impact protein function (Al-Tassan 2002 PMID: 11818965, Ali 2008 PMID: 18534194, Goto 2010 PMID: 20848659). Computational prediction tools and conservation analysis suggest that the p.Gly396Asp variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for MUTYH-associated polyposis in an autosomal recessive manner. The ACMG/AMP Criteria applied: PM3_VeryStrong, PP3, PS3_Supporting. (less)
Pathogenic (Jul 31, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV002547276.7 First in ClinVar: Jul 17, 2022 Last updated: Aug 04, 2024
Pathogenic (Apr 11, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005199293.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Nov 20, 2015)	criteria provided, single submitter (Shirts et al. (Genet Med 2016)) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: no Allele origin: germline	University of Washington Department of Laboratory Medicine, University of Washington Accession: SCV000266099.1 First in ClinVar: Mar 20, 2016 Last updated: Mar 20, 2016	Observation 1: Number of individuals with the variant: 1 Observation 2: Number of individuals with the variant: 1
Pathogenic (Jul 01, 2015)	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015)) Method: clinical testing	Familial adenomatous polyposis 2 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000678192.1 First in ClinVar: Jan 06, 2018 Last updated: Jan 06, 2018	Publications: PubMed (5) PubMed: 19732775‚ 11818965‚ 19953527‚ 21178863‚ 18534194
Pathogenic (Nov 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial adenomatous polyposis 2 Affected status: yes Allele origin: germline	Center for Human Genetics, Inc, Center for Human Genetics, Inc Accession: SCV000781800.1 First in ClinVar: Jul 07, 2018 Last updated: Jul 07, 2018
Pathogenic (May 23, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. Accession: SCV000679736.2 First in ClinVar: Dec 19, 2017 Last updated: Aug 04, 2018
Pathogenic (Jan 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ovarian carcinoma Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001440759.1 First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020
Pathogenic (Apr 02, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial adenomatous polyposis 2 Affected status: yes Allele origin: germline	Department of Molecular Diagnostics, Institute of Oncology Ljubljana Accession: SCV001499746.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021
Pathogenic (-)	criteria provided, single submitter (ACGS Guidelines, 2016) Method: clinical testing	Familial adenomatous polyposis 2 Affected status: yes Allele origin: germline	Genomics England Pilot Project, Genomics England Accession: SCV001760033.1 First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021
Likely pathogenic (Aug 31, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial adenomatous polyposis 2 Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001934278.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Pathogenic (May 05, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000149657.14 First in ClinVar: May 17, 2014 Last updated: Feb 19, 2018	Comment: Observed in the homozygous and compound heterozygous state in multiple individuals with MUTYH-Associated Polyposis, including affected siblings (Al-Tassan 2002, Win 2016, de Leon 2017, Furlan … (more) Observed in the homozygous and compound heterozygous state in multiple individuals with MUTYH-Associated Polyposis, including affected siblings (Al-Tassan 2002, Win 2016, de Leon 2017, Furlan 2017, Yurgelun 2017); Published functional studies demonstrate a damaging effect: reduced glycosylase and DNA binding activity (Ali 2008, Goto 2010, Ruggieri 2013, Komine 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20687945, 21063410, 21952991, 22926731, 21178863, 20418187, 23361220, 28195393, 11818965, 29330641, 30564557, 32231684, 30582135, 18534194, 23108399, 20848659, 22703879, 19836313, 22744763, 19998059, 19732775, 19032956, 19953527, 22473953, 23625202, 23805267, 24082139, 22158503, 19245865, 27014339, 27194394, 26202870, 27631816, 27696107, 27705013, 27313931, 28135145, 27829682, 17039270, 24728327, 28127763, 27783336, 28141798, 27870730, 25820570, 27153395, 26332594, 26822237, 26681312, 28687356, 28944238, 28503720, 25186627, 28577310, 29371908, 29766397, 28634180, 29785153, 28152038, 26556299, 29915346, 29406563, 29958926, 30067863, 30333958, 30609409, 30256826, 30702970, 30620386, 29978187, 30322717, 30309722, 30604180, 30833417, 31159747, 30676620, 31285513, 30877237, 31512090, 30306255, 32088803, 30291343, 28709830, 31618753, 31447099, 31263571, 32854451, 31980526, 33384714, 32338768, 33258288, 32830346, 33504652) (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial adenomatous polyposis 2 Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV002073195.1 First in ClinVar: Feb 05, 2022 Last updated: Feb 05, 2022	Comment: The missense variant p.G396D in MUTYH (NM_001128425.2) has been observed in homozygous or compound heterozygous form with other pathogenic MUTYH variants in patients with adenomatous … (more) The missense variant p.G396D in MUTYH (NM_001128425.2) has been observed in homozygous or compound heterozygous form with other pathogenic MUTYH variants in patients with adenomatous polyposis syndrome (Al-Tassan 2002, Ruggieri 2013). Functional characterization of the variant protein indicates a partial reduction in DNA binding and glycosylase activity (Ruggieri 2013). The observed variant has been reported in ClinVar as Pathogenic. The p.G396D variant is observed in 555/1,12,884 (0.4917%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and in 9/1,006 (0.8946%) alleles from individuals of European background in 1000 Genomes, which is greater than expected for the disorder. There is a moderate physicochemical difference between glycine and aspartic acid. The p.G396D missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.1187 in MUTYH is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less) Clinical Features: Cerebellar ataxia (present) , Dystonic disorder (present) , Spasticity (present) , Nystagmus (present) , Cerebellar atrophy (present) , Telangiectasia (present) , Reduced tendon reflexes (present)
Pathogenic (Mar 25, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial colorectal cancer Affected status: yes Allele origin: germline	DASA Accession: SCV002318970.1 First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022	Publications: PubMed (12) PubMed: 15987719‚ 18534194‚ 20848659‚ 23108399‚ 23035301‚ 19394335‚ 21171015‚ 24444654‚ 15931596‚ 11818965‚ 16557584‚ 17489848 Comment: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 15987719; 18534194; 20848659; 23108399) - … (more) Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 15987719; 18534194; 20848659; 23108399) - PS3_moderate. The c.1187G>A;p.(Gly396Asp)The c.1187G>A;p.(Gly396Asp) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 5294; PMID: 23035301; PMID: 19394335; PMID: 21171015; PMID: 24444654; PMID: 15931596) - PS4. The variant co-segregated with disease in multiple affected family members (PMID: 11818965, 16557584, 17489848) - PP1_strong. In summary, the currently available evidence indicates that the variant is pathogenic. (less) Number of individuals with the variant: 1 Sex: female Geographic origin: Brazil
Pathogenic (Aug 06, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial adenomatous polyposis 2 Affected status: no Allele origin: germline	National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health Accession: SCV002522174.1 First in ClinVar: Jun 05, 2022 Last updated: Jun 05, 2022
Pathogenic (May 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Familial adenomatous polyposis 2 Affected status: unknown Allele origin: unknown	Laan Lab, Human Genetics Research Group, University of Tartu Accession: SCV002538610.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022	Publications: PubMed (1) PubMed: 35535697 Number of individuals with the variant: 1 Clinical Features: Non-obstructive azoospermia (present) Secondary finding: yes Method: exome sequencing
Pathogenic (Jul 05, 2022)	criteria provided, single submitter (St. Jude Assertion Criteria 2020) Method: clinical testing	Familial adenomatous polyposis 2 Affected status: unknown Allele origin: germline	St. Jude Molecular Pathology, St. Jude Children's Research Hospital Accession: SCV002525942.2 First in ClinVar: Jun 18, 2022 Last updated: Oct 22, 2022	Comment: The MUTYH c.1187G>A (p.Gly396Asp) missense change is a well-established pathogenic variant for MUTYH-associated polyposis and is estimated to account for up to 80% of cases … (more) The MUTYH c.1187G>A (p.Gly396Asp) missense change is a well-established pathogenic variant for MUTYH-associated polyposis and is estimated to account for up to 80% of cases in European patients (PMID: 23035301). Although MUTYH-associated polyposis is typically caused by biallelic variants affecting the MUTYH gene, there is evidence that monoallelic pathogenic MUTYH variants including this particular variant are associated with increased risk of colon cancer (PMID: 16492921, 19394335, 21171015, 24444654, 15931596). This variant has a maximum subpopulation frequency of 0.49% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, and functional studies have shown that this missense change disrupts MUTYH protein function (PMID: 15987719, 18534194, 20848659, 23108399). This variant has been reported to co-segregate with disease in individuals affected with colorectal cancer and polyposis (with polyp numbers ranging from 10 to >100) (PMID: 11818965, 16557584, 17489848, 19793053). In summary, this variant meets criteria to be classified as pathogenic. (less)
Pathogenic (Oct 31, 2022)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000604306.8 First in ClinVar: Jun 09, 2014 Last updated: Mar 04, 2023	Comment: The MUTYH c.1187G>A; p.Gly396Asp variant (rs36053993; also known as NM_001048171.1: c.1145G>A; p.Gly382Asp) has been well described in the literature as one of the two common … (more) The MUTYH c.1187G>A; p.Gly396Asp variant (rs36053993; also known as NM_001048171.1: c.1145G>A; p.Gly382Asp) has been well described in the literature as one of the two common MUTYH pathogenic variants. It has been observed in homozygous or compound heterozygous form with other pathogenic MUTYH variants in patients with adenomatous polyposis syndrome (Al-Tassan 2002, Nielsen 2009, Ruggieri 2013), and is enriched in patients with an odds ratio of 6.47 (Theodoratou 2010). Functional characterization of the variant protein indicates a partial reduction in DNA binding and glycosylase activity (Ali 2008, D'Agostino 2010, Goto 2010, Komine 2015, Kundu 2009, Molatore 2010, Ruggieri 2013). Based on available information, this variant is considered to be pathogenic. References: Ali M et al. Characterization of mutant MUTYH proteins associated with familial colorectal cancer. Gastroenterology. 2008 135(2):499-507. PMID: 18534194. Al-Tassan N et al. Inherited variants of MYH associated with somatic G:C-->T:A mutations in colorectal tumors. Nat Genet. 2002 30(2):227-32. PMID: 11818965 D'Agostino V et al. Functional analysis of MUTYH mutated proteins associated with familial adenomatous polyposis. DNA Repair (Amst). 2010 9(6):700-7. PMID: 20418187. Goto M et al. Adenine DNA glycosylase activity of 14 human MutY homolog (MUTYH) variant proteins found in patients with colorectal polyposis and cancer. Hum Mutat. 2010 31(11):E1861-74. PMID: 20848659. Komine K et al. Functional Complementation Assay for 47 MUTYH Variants in a MutY-Disrupted Escherichia coli Strain. Hum Mutat. 2015 36(7):704-11. PMID: 25820570. Kundu S et al. Adenine removal activity and bacterial complementation with the human MutY homologue (MUTYH) and Y165C, G382D, P391L and Q324R variants associated with colorectal cancer. DNA Repair (Amst). 2009 8(12):1400-10. PMID: 19836313. Molatore S et al. MUTYH mutations associated with familial adenomatous polyposis: functional characterization by a mammalian cell-based assay. Hum Mutat. 2010 31(2):159-66. PMID: 19953527. Nielsen M et al. Analysis of MUTYH genotypes and colorectal phenotypes in patients With MUTYH-associated polyposis. Gastroenterology. 2009 136(2):471-6. PMID: 19032956. Ruggieri V et al. Loss of MUTYH function in human cells leads to accumulation of oxidative damage and genetic instability. Oncogene. 2013 32(38):4500-8. PMID: 23108399. Theodoratou E et al. A large-scale meta-analysis to refine colorectal cancer risk estimates associated with MUTYH variants. Br J Cancer. 2010 Dec 7;103(12):1875-84. PMID: 21063410. (less)
Pathogenic (May 31, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial adenomatous polyposis 2 Affected status: no Allele origin: germline	KCCC/NGS Laboratory, Kuwait Cancer Control Center Accession: SCV003927260.1 First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023	Comment: (p.Gly396Asp). This variant is present in population databases (rs36053993, gnomAD 0.5%), including at least one homozygous and/or hemizygous individual. This variant is a known common … (more) (p.Gly396Asp). This variant is present in population databases (rs36053993, gnomAD 0.5%), including at least one homozygous and/or hemizygous individual. This variant is a known common cause of MUTYH-associated polyposis (PMID: 23035301). This variant has been reported to co-segregate with disease in individuals affected with colorectal cancer and polyposis (with polyp numbers ranging from 10 to >100) (PMID: 11818965, 16557584, 17489848, 19793053). MUTYH-related conditions are inherited in an autosomal recessive fashion. However, there is evidence that monoallelic pathogenic MUTYH variants including this particular variant associated with increased risk of colon cancer (PMID: 16492921, 19394335, 21171015, 24444654, 15931596). This variant is also known as c.1145G>A (p.Gly382Asp). ClinVar contains an entry for this variant (Variation ID: 5294). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PoIyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MUTYH function (PMID: 15987719, 18534194, 20848659, 23108399). For these reasons, this variant has been classified as Pathogenic. Pathogcnic/likely pathogenic mutations in the MUTYH gene are associated with familial polyposis syndrome. (less) Age: 60-69 years Sex: female
Pathogenic (Aug 31, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial adenomatous polyposis 2 (Autosomal recessive inheritance) Affected status: unknown Allele origin: unknown	Intergen, Intergen Genetics and Rare Diseases Diagnosis Center Accession: SCV004031104.1 First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023
Pathogenic (Dec 20, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial adenomatous polyposis 2 Affected status: unknown Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV002512303.2 First in ClinVar: May 21, 2022 Last updated: Dec 24, 2023	Comment: ACMG classification criteria: PS3, PS4, PM3, PP1 Geographic origin: Brazil
Pathogenic (May 03, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000691947.4 First in ClinVar: Feb 19, 2018 Last updated: Jan 26, 2024	Publications: PubMed (8) PubMed: 11818965‚ 15987719‚ 16557584‚ 18534194‚ 19032956‚ 19245865‚ 19732775‚ 20848659 Comment: PP1_strong, PP4, PM3, PS3_supporting, PS4_moderate Number of individuals with the variant: 57
Pathogenic (Feb 06, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000537630.5 First in ClinVar: Mar 24, 2017 Last updated: Feb 14, 2024	Publications: PubMed (12) PubMed: 11818965‚ 12606733‚ 15036665‚ 15635083‚ 15987719‚ 16557584‚ 20848659‚ 23361220‚ 25590978‚ 27783336‚ 28135145‚ 29147111 Comment: This missense variant replaces glycine with aspartic acid at codon 396 of the MUTYH protein. This variant is also known as p.Gly382Asp (c.1145G>A) based on … (more) This missense variant replaces glycine with aspartic acid at codon 396 of the MUTYH protein. This variant is also known as p.Gly382Asp (c.1145G>A) based on an alternate transcript NM_001048171. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). Functional studies have shown that the mutant protein exhibits significantly reduced activity in in vitro DNA glycosylase activity assay (PMID: 15036665, 15987719, 20848659). This variant is a well-established pathogenic variant known to cause adenomatous polyposis and colorectal cancer in homozygous or compound heterozygous individuals (PMID: 11818965, 12606733, 15635083, 16557584, 23361220, 25590978, 27783336, 28135145, 29147111). This variant is one of two most common pathogenic MUTYH variants, which together account for up to 80% of MUTYH-associated disease observed in Caucasian individuals (PMID: 29147111). This variant has been identified in 860/281146 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
Pathogenic (Dec 18, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000184573.10 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Publications: PubMed (7) PubMed: 19032956‚ 21063410‚ 21952991‚ 22297469‚ 22473953‚ 22926731‚ 23108399 Comment: The c.1187G>A (p.G396D) alteration is located in coding exon 13 of the MUTYH gene. This alteration results from a G to A substitution at nucleotide … (more) The c.1187G>A (p.G396D) alteration is located in coding exon 13 of the MUTYH gene. This alteration results from a G to A substitution at nucleotide position 1187, causing the glycine (G) at amino acid position 396 to be replaced by an aspartic acid (D). Based on data from gnomAD, the A allele has an overall frequency of 0.306% (860/281146) total alleles studied. The highest observed frequency was 0.489% (628/128314) of European (non-Finnish) alleles. This mutation has been identified in a significant percentage of individuals with MUTYH-associated polyposis and represents a founder mutation in multiple populations (Nielsen, 2009). Of the 12 individuals reported as p.G396D homozygotes by these authors, the mean age at clinical presentation was 51 years (range of 36-62). Nine of these 12 individuals had a history of colorectal cancer with a mean age at diagnosis of 58 years (range of 37-70). This amino acid position is highly conserved in available vertebrate species. Functional analysis demonstrated that the p.G396D alteration does not affect protein expression or splicing, but results in significantly reduced oxidative DNA mismatch repair efficiency compared to wild type (Plotz, 2012; Raetz, 2012; Ruggieri, 2013). RNA studies have demonstrated this alteration does not result in abnormal splicing in the set of samples tested (Ambry internal data). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
Pathogenic (Mar 29, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial adenomatous polyposis 2 Affected status: unknown Allele origin: unknown	Baylor Genetics Study: CSER-TexasKidsCanSeq Accession: SCV001482742.2 First in ClinVar: Mar 07, 2021 Last updated: Jun 17, 2024
Pathogenic (Aug 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001248078.25 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: MUTYH: PS3, PS4, PM1, PP3 Number of individuals with the variant: 61
Pathogenic (Nov 04, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial adenomatous polyposis 2 Affected status: unknown Allele origin: germline	Institute of Immunology and Genetics Kaiserslautern Accession: SCV005382145.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024	Comment: ACMG Criteria: PS3, PS4, PM3, PM5, PP3, PP5; Variant was found in heterozygous state. Clinical Features: Malignant tumor of prostate (present)
Pathogenic (Jul 26, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Diffuse midline glioma, H3 K27-altered Affected status: yes Allele origin: germline	Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital Accession: SCV005381829.1 First in ClinVar: Nov 17, 2024 Last updated: Nov 17, 2024
pathogenic (Jul 13, 2012)	no assertion criteria provided Method: research	MYH-associated polyposis Affected status: no Allele origin: germline	Biesecker Lab/Clinical Genomics Section, National Institutes of Health Study: ClinSeq Accession: SCV000043370.1 First in ClinVar: Apr 12, 2013 Last updated: Apr 12, 2013	Publications: PubMed (1) PubMed: 22703879 Comment: Converted during submission to Pathogenic. Number of individuals with the variant: 4 Comment on evidence: The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for … (more) The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for details. (less)
Pathogenic (Jun 04, 2015)	no assertion criteria provided Method: research	Familial adenomatous polyposis 2 Gastric cancer Affected status: unknown Allele origin: germline	Division of Human Genetics, Children's Hospital of Philadelphia Study: CSER-PediSeq Accession: SCV000536693.1 First in ClinVar: Apr 23, 2017 Last updated: Apr 23, 2017	Publications: PubMed (23) PubMed: 11818965‚ 22744763‚ 18534194‚ 23361220‚ 24728327‚ 23805267‚ 20418187‚ 24082139‚ 20848659‚ 19998059‚ 22703879‚ 23625202‚ 19836313‚ 19953527‚ 21178863‚ 19032956‚ 22473953‚ 22926731‚ 21952991‚ 23108399‚ 21063410‚ 19732775‚ 22158503
Pathogenic (Sep 01, 2011)	no assertion criteria provided Method: literature only	ENDOMETRIAL CANCER Affected status: not provided Allele origin: germline	OMIM Accession: SCV000025797.3 First in ClinVar: Apr 04, 2013 Last updated: Sep 08, 2019	Publications: PubMed (4) PubMed: 11818965‚ 17956577‚ 12606733‚ 21815886 Comment on evidence: For discussion of the gly382-to-asp (G382D) mutation in the MUTYH gene that was found in compound heterozygous state in patients with familial adenomatous polyposis-2 (FAP2; … (more) For discussion of the gly382-to-asp (G382D) mutation in the MUTYH gene that was found in compound heterozygous state in patients with familial adenomatous polyposis-2 (FAP2; 608456) by Al-Tassan et al. (2002) and in a patient with endometrial adenocarcinoma (see 608089) by Barnetson et al. (2007), see 604933.0001. Sieber et al. (2003) found the G382D mutation in compound heterozygous or homozygous state in 6 patients in the UK with multiple colorectal adenomas (608456). In a 45-year-old French man who was found to have 25 colorectal adenomas on colonoscopy, Rouleau et al. (2011) identified compound heterozygosity for G382D and a large rearrangement of the MUTYH gene resulting in the deletion of exons 3 to 16 (604933.0009). (less)
Pathogenic (Sep 01, 2011)	no assertion criteria provided Method: literature only	FAMILIAL ADENOMATOUS POLYPOSIS 2 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000025796.3 First in ClinVar: Apr 04, 2013 Last updated: Sep 08, 2019	Publications: PubMed (4) PubMed: 11818965‚ 17956577‚ 12606733‚ 21815886 Comment on evidence: For discussion of the gly382-to-asp (G382D) mutation in the MUTYH gene that was found in compound heterozygous state in patients with familial adenomatous polyposis-2 (FAP2; … (more) For discussion of the gly382-to-asp (G382D) mutation in the MUTYH gene that was found in compound heterozygous state in patients with familial adenomatous polyposis-2 (FAP2; 608456) by Al-Tassan et al. (2002) and in a patient with endometrial adenocarcinoma (see 608089) by Barnetson et al. (2007), see 604933.0001. Sieber et al. (2003) found the G382D mutation in compound heterozygous or homozygous state in 6 patients in the UK with multiple colorectal adenomas (608456). In a 45-year-old French man who was found to have 25 colorectal adenomas on colonoscopy, Rouleau et al. (2011) identified compound heterozygosity for G382D and a large rearrangement of the MUTYH gene resulting in the deletion of exons 3 to 16 (604933.0009). (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001977685.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001980277.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001979836.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
Pathogenic (Oct 09, 2023)	no assertion criteria provided Method: clinical testing	Familial adenomatous polyposis 2 Affected status: yes Allele origin: germline	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas Accession: SCV004041729.1 First in ClinVar: Oct 14, 2023 Last updated: Oct 14, 2023
Pathogenic (Sep 10, 2024)	no assertion criteria provided Method: clinical testing	MUTYH-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000806339.4 First in ClinVar: Sep 13, 2018 Last updated: Oct 08, 2024	Comment: The MUTYH c.1187G>A variant is predicted to result in the amino acid substitution p.Gly396Asp. This variant, alternatively described as “G382D or Gly382Asp”, is one of … (more) The MUTYH c.1187G>A variant is predicted to result in the amino acid substitution p.Gly396Asp. This variant, alternatively described as “G382D or Gly382Asp”, is one of the most common pathogenic variants in MUTYH-associated polyposis (MAP) (Plotz et al. 2012. PubMed ID: 22473953; Olfson et al. 2015. PubMed ID: 26332594; Fabišíková et al. 2020. PubMed ID: 33384714; Daans et al. 2020. PubMed ID: 32088803; Curia et al. 2020. PubMed ID: 32821650). Functional (in vitro) studies of this variant have shown that it negatively affects protein function (Al-Tassan et al. 2002. PubMed ID: 11818965; Goto et al. 2010. PubMed ID: 20848659). However, this variant has been reported with a subpopulation frequency up to ~0.5%, including three homozygotes, in gnomAD. In ClinVar, the vast majority of clinical laboratories have classified this variant as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/5294/). Based on the collective evidence, we interpret this variant as pathogenic. (less)
Pathogenic (Jul 24, 2014)	no assertion criteria provided Method: clinical testing	Carcinoma of colon Affected status: unknown Allele origin: germline	Pathway Genomics Accession: SCV000189964.1 First in ClinVar: Oct 19, 2014 Last updated: Oct 19, 2014	Publications: PubMed (5) PubMed: 19032956‚ 19732775‚ 19394335‚ 11818965‚ 19836313
Likely pathogenic (Mar 09, 2017)	no assertion criteria provided Method: case-control	Small intestine carcinoid (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Endocrine oncology group, Uppsala University Accession: SCV000536689.1 First in ClinVar: Jul 02, 2017 Last updated: Jul 02, 2017	Publications: PubMed (1) PubMed: 28634180 Number of individuals with the variant: 6 Age: 23-90 years Sex: mixed Ethnicity/Population group: caucasian Geographic origin: Sweden
Pathogenic (Oct 12, 2015)	no assertion criteria provided Method: research	Familial adenomatous polyposis 2 GERMLINE (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Donald Williams Parsons Laboratory, Baylor College of Medicine Additional submitter: Donald Williams Parsons Laboratory, Baylor College of Medicine Study: CSER-BASIC3 Accession: SCV000599972.1 First in ClinVar: Aug 27, 2017 Last updated: Aug 27, 2017	Publications: PubMed (24) PubMed: 26822237‚ 11818965‚ 22703879‚ 21063410‚ 21952991‚ 22926731‚ 21178863‚ 20418187‚ 19836313‚ 23361220‚ 22744763‚ 19998059‚ 18534194‚ 19732775‚ 19032956‚ 19953527‚ 20848659‚ 22473953‚ 23625202‚ 23108399‚ 24728327‚ 23805267‚ 24082139‚ 22158503 Comment: This variant has been previously reported as disease-causing. It would be pathogenic in a recessive state; heterozygotes would be carriers for the condition. It was … (more) This variant has been previously reported as disease-causing. It would be pathogenic in a recessive state; heterozygotes would be carriers for the condition. It was found once in our study heterozygous in a 6-year-old male with anaplastic ganglioglioma. (less) Number of individuals with the variant: 1 Age: 0-9 years Sex: male
Pathogenic (Dec 29, 2017)	no assertion criteria provided Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	True Health Diagnostics Accession: SCV000788060.1 First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Carcinoma of colon Affected status: yes Allele origin: unknown	Department of Pathology and Laboratory Medicine, Sinai Health System Additional submitter: Franklin by Genoox Study: The Canadian Open Genetics Repository (COGR) Accession: SCV000592711.2 First in ClinVar: Aug 27, 2017 Last updated: Apr 13, 2021	Comment: The p.Gly396Asp variant was identified in 102 of 1112 proband chromosomes (frequency: 0.092) from individuals or families with colorectal cancer or MUTYH-associated polyposis, and was … (more) The p.Gly396Asp variant was identified in 102 of 1112 proband chromosomes (frequency: 0.092) from individuals or families with colorectal cancer or MUTYH-associated polyposis, and was not identified in 264 control chromosomes from healthy individuals (Eliason 2006, Nielsen 2009, Sieber 2003). The p.Gly396Asp variant was also identified by our laboratory in 22 individuals with colorectal cancer or polyposis. The p.Gly396Asp variant was identified in dbSNP (ID:rs36053993 ) â€šÃ„ÃºWith pathogenic alleleâ€šÃ„Ã¹, with a minor allele frequency of 0.004 (1000 Genomes Project ), NHLBI Exome Sequencing Project (Exome Variant Server) in 50 of 13006 alleles (frequency: 0.004), HGMD, the â€šÃ„ÃºInSiGHT Colon Cancer Databaseâ€šÃ„Ã¹, and UMD (518X as a causal variant; co-occurring with 14 different pathogenic variants). The p.Gly396Asp variant was classified as a pathogenic variant by multiple submitters to the ClinVar database, including OMIM, GeneReviews, and Emory Genetics. The p.Gly396Asp variant occurs in the first base of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing and in-silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a significant difference in splicing. The p.Gly396 residue is conserved across mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Gly396Asp variant may impact the protein. In vitro assays using synthetic DNA substrates showed that the variant protein reduced adenine removal activity as compared to the wild-type protein and was partially active in DNA binding, base excision repair (BER) and glycosylase activities (Ali 2008, D'Agostino 2010). Two bacterial or mammalian cell-based studies by Kundu (2009) and Molatare (2009) found that the glycosylase activity of the p.Gly396Asp variant did not differ significantly from wild-type; however, Kundu (2009) suggests that the activity of the variant may be more reduced in human cells. Nielsen (2009) identified that although the phenotypic effects of the variant are relatively mild, there is a significantly greater colorectal cancer hazard for patients who were compound heterozygotes for this and a variant with truncating or certain other missense mutations. In summary, based on the above information, this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic (less) Number of individuals with the variant: 24
Pathogenic (Aug 20, 2021)	no assertion criteria provided Method: clinical testing	Breast carcinoma Affected status: yes Allele origin: germline	Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences Accession: SCV001797301.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021	Comment: Invasive Ductal Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Positive HER2 Receptor: Negative Age: 30-39 years
Pathogenic (Aug 23, 2021)	no assertion criteria provided Method: clinical testing	Colon cancer Affected status: yes Allele origin: germline	Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences Accession: SCV001805860.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021	Comment: Colon Cancer Age: 40-49 years
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001744816.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001977647.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001979292.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002037440.1 First in ClinVar: Dec 25, 2021 Last updated: Dec 25, 2021
not provided (Sep 19, 2013)	no classification provided Method: reference population	AllHighlyPenetrant Affected status: unknown Allele origin: germline	ITMI Accession: SCV000085795.1 First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 Comment: Please see associated publication for description of ethnicities	Publications: PubMed (1) PubMed: 24728327 Observation 1: Ethnicity/Population group: Whole_cohort Observation 2: Ethnicity/Population group: African Observation 3: Ethnicity/Population group: African_European Observation 4: Ethnicity/Population group: Central_Asian Observation 5: Ethnicity/Population group: East_Asian Observation 6: Ethnicity/Population group: European Observation 7: Ethnicity/Population group: Hispanic
not provided (-)	no classification provided Method: phenotyping only	MUTYH-associated polyposis Affected status: unknown Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV000840099.1 First in ClinVar: Oct 13, 2018 Last updated: Oct 13, 2018	Comment: GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical … (more) GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Clinical Features: Hypermetropia (present) , Myopia (present) , Abnormality of vision (present) , Abnormality of the lens (present) , Abnormality of the urethra (present) , Abnormality of … (more) Hypermetropia (present) , Myopia (present) , Abnormality of vision (present) , Abnormality of the lens (present) , Abnormality of the urethra (present) , Abnormality of the female genitalia (present) , Abnormality of the bladder (present) , Breast carcinoma (present) (less) Indication for testing: Diagnostic Age: 60-69 years Sex: female Method: Sanger Sequencing Testing laboratory: GeneDx Date variant was reported to submitter: 2017-07-08 Testing laboratory interpretation: Pathogenic
not provided (-)	no classification provided Method: phenotyping only	Familial adenomatous polyposis 2 Affected status: unknown Allele origin: unknown	GenomeConnect - Invitae Patient Insights Network Accession: SCV001716323.1 First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021	Comment: Variant reported in multiple Invitae PIN participants by multiple clinical testing laboratories. Variant interpreted as Pathogenic by all laboratories and reported most recently on 10/09/20 … (more) Variant reported in multiple Invitae PIN participants by multiple clinical testing laboratories. Variant interpreted as Pathogenic by all laboratories and reported most recently on 10/09/20 by Invitae and 11/4/14 by Ambry Genetics GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. (less) Observation 1: Number of individuals with the variant: 1 Clinical Features: Myopia (present) , Abnormal retinal morphology (present) , Abnormality of the female genitalia (present) Indication for testing: Diagnostic Age: 50-59 years Sex: female Testing laboratory: Invitae Date variant was reported to submitter: 2019-10-21 Testing laboratory interpretation: Pathogenic Observation 2: Number of individuals with the variant: 1 Clinical Features: Breast carcinoma (present) Indication for testing: Diagnostic Age: 40-49 years Sex: female Testing laboratory: Invitae Date variant was reported to submitter: 2019-10-27 Testing laboratory interpretation: Pathogenic Observation 3: Number of individuals with the variant: 1 Clinical Features: Hypermetropia (present) , Abnormality of vision (present) , Tinnitus (present) , Abnormal oral cavity morphology (present) , Hyperpigmentation of the skin (present) , Asthma (present) … (more) Hypermetropia (present) , Abnormality of vision (present) , Tinnitus (present) , Abnormal oral cavity morphology (present) , Hyperpigmentation of the skin (present) , Asthma (present) , Bleeding with minor or no trauma (present) , Bruising susceptibility (present) , Persistent bleeding after trauma (present) , Autoimmunity (present) , Abnormal inflammatory response (present) , Obesity (present) , Abnormal limb bone morphology (present) , Abnormal curvature of the vertebral column (present) , Hyperthyroidism (present) , Abnormality of the parathyroid physiology (present) , Abnormal delivery (present) (less) Indication for testing: Presymptomatic Age: 70-79 years Sex: female Testing laboratory: Invitae Date variant was reported to submitter: 2020-03-22 Testing laboratory interpretation: Pathogenic Observation 4: Number of individuals with the variant: 1 Clinical Features: Family history of cancer (present) Indication for testing: Diagnostic Age: 50-59 years Sex: female Testing laboratory: Invitae Date variant was reported to submitter: 2020-10-09 Testing laboratory interpretation: Pathogenic Observation 5: Number of individuals with the variant: 1 Clinical Features: Breast carcinoma (present) Indication for testing: Diagnostic Age: 40-49 years Sex: female Testing laboratory: Ambry Genetics Date variant was reported to submitter: 2014-11-04 Testing laboratory interpretation: Pathogenic
not provided (-)	no classification provided Method: literature only	Familial adenomatous polyposis 2 Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000057867.6 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: PubMed (4) PubMed: 23035301‚ 11818965‚ 19245865‚ 19032956 BookShelf: NBK107219 BookShelf: NBK107219 Comment: Common pathogenic variants carried by approximately 1%-2% of the general population that account for ≥90% of all MUTYH pathogenic variants in northern European populations; ≤70% … (more) Common pathogenic variants carried by approximately 1%-2% of the general population that account for ≥90% of all MUTYH pathogenic variants in northern European populations; ≤70% of persons with MUTYH-Associated Polyposis (MAP) harbor at least 1 of these variants, 536A>G or 1187G>A (less)
click to load more click to collapse

Comment:

This sequence change replaces Glycine with Aspartic acid at codon 396 of the MUTYH protein. The glycine residue is highly conserved in the Nudix Hydrolase domain of the protein and there is a moderate physiochemical difference between glycine and aspartic acid (Grantham Score 94).This variant is present in population databases (rs36053993, 0.4%) and has been reported in the literature. This variant has been reported to co-segregate with disease in patients affected with colorectal cancer, familial adenomatous polyposis (FAP), and attenuated FAP (PMID: 31159747, 19793053, 11818965 ) when found in the homozygous state or in compound heterozygosis with another MUTYH pathogenic variant. This variant is also known as c.1145G>A (p.Gly382Asp) in the literature. Experimental studies have shown that this missense change disrupts MUTYH protein function (PMID: 20848659 ; 15987719). The mutation databaseClinVar contains entries for this variant (Variation ID:5294).

Comment:

Variant summary: MUTYH c.1187G>A (p.Gly396Asp) results in a non-conservative amino acid change located in the NUDIX hydrolase domain (IPR000086) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.003 in 250814 control chromosomes in the gnomAD database, including 3 homozygotes. c.1187G>A has been reported in the literature in multiple individuals affected with MUTYH-Associated Polyposis (example: Castillejo_2014, DeLellis_2013, Ricci_2016). These data indicate that the variant is very likely to be associated with disease. Functional studies support a damaging outcome, and at least 2 independent labs have down reduced DNA glycosylase activity and a reduced ability to suppress the mutation frequency in a complementation assay (example: Goto_2010, Komine_2015, Kundu_2009). 32 ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

The MUTYH c.1187G>A (p.Gly396Asp) variant (also known as G396D and G382D) has been reported in the published literature in multiple cases of MUTYH-Associated Polyposis (MAP). This variant is one of two pathogenic variants associated with at least 90% of cases of MAP in patients of European ancestry (PMIDs: 19032956 (2009), 22744763 (2012), 23361220 (2014), 28135145 (2017), 28944238 (2017), 29766397 (2018), 30604180 (2019)). Furthermore, this variant has been described to have a damaging effect on DNA binding and DNA glycosylase activity of the MUTYH protein (PMIDs: 18534194 (2008), 19032956 (2009), 19953527 (2010), 20418187 (2010), 25820570 (2015)). Based on the available information, this variant is classified as pathogenic.

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 396 of the MUTYH protein (p.Gly396Asp). This variant is present in population databases (rs36053993, gnomAD 0.5%), including at least one homozygous and/or hemizygous individual. This variant is a known common cause of MUTYH-associated polyposis (PMID: 23035301). This variant has been reported to co-segregate with disease in individuals affected with colorectal cancer and polyposis (with polyp numbers ranging from 10 to >100) (PMID: 11818965, 16557584, 17489848, 19793053). MUTYH-related conditions are inherited in an autosomal recessive fashion. However, there is evidence that monoallelic pathogenic MUTYH variants including this particular variant are associated with increased risk of colon cancer (PMID: 16492921, 19394335, 21171015, 24444654, 15931596). This variant is also known as c.1145G>A (p.Gly382Asp). ClinVar contains an entry for this variant (Variation ID: 5294). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MUTYH function (PMID: 15987719, 18534194, 20848659, 23108399). For these reasons, this variant has been classified as Pathogenic.

Comment:

The c.1187G>A (p.Gly396Asp) variant in the MUTYH gene is located on the exon 13 and is predicted to replace glycine with aspartic acid at codon 396 of the MUTYH protein. This variant has been observed in homozygous or compound heterozygous state in multiple individuals with MUTYH-associated polyposis and colorectal cancer (PMID: 11818965, 12606733, 15635083, 16557584, 19032956, 23108399, 23361220, 25590978, 26202870, 27783336, 28135145, 29147111). This variant has been reported to co-segregate with disease in multiple individuals (PMID: 11818965, 16557584, 17489848, 19793053, 31159747). Experimental studies have shown that this variant affects MUTYH function and leads to a reduction in DNA binding and glycosylase activity (PMID: 11818965, 15036665, 15987719, 18534194, 20418187, 20848659, 22473953, 22926731, 23108399, 25820570). This missense change has been identified in 860/281146 chromosomes in the general population by the Genome Aggregation Database (gnomAD), including three homozygotes. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (REVEL score = 0.954). Based on these evidence, the c.1187G>A (p.Gly396Asp) variant in the MUTYH gene is classified as pathogenic.

Comment:

The p.Gly396Asp variant in MUTYH is a well-established pathogenic variant for MUTYH-related attenuated familial adenomatous polyposis and is estimated to account for 50-82% of MUTYH-associated polyposis in European patients (Al-Tassan 2002 PMID: 11818965, Nielsen 2009 PMID: 17489848, Vogt 2009 PMID: 19732775, Nascimbeni 2010 PMID: 21178863, Aretz 2014 PMID: 23361220, ClinVar: Variation ID 5294). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 5294) and has been identified in 0.5% (367/68040) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2); however, this frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the p.Gly396Asp variant may impact protein function (Al-Tassan 2002 PMID: 11818965, Ali 2008 PMID: 18534194, Goto 2010 PMID: 20848659). Computational prediction tools and conservation analysis suggest that the p.Gly396Asp variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for MUTYH-associated polyposis in an autosomal recessive manner. The ACMG/AMP Criteria applied: PM3_VeryStrong, PP3, PS3_Supporting.

Comment:

Observed in the homozygous and compound heterozygous state in multiple individuals with MUTYH-Associated Polyposis, including affected siblings (Al-Tassan 2002, Win 2016, de Leon 2017, Furlan 2017, Yurgelun 2017); Published functional studies demonstrate a damaging effect: reduced glycosylase and DNA binding activity (Ali 2008, Goto 2010, Ruggieri 2013, Komine 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20687945, 21063410, 21952991, 22926731, 21178863, 20418187, 23361220, 28195393, 11818965, 29330641, 30564557, 32231684, 30582135, 18534194, 23108399, 20848659, 22703879, 19836313, 22744763, 19998059, 19732775, 19032956, 19953527, 22473953, 23625202, 23805267, 24082139, 22158503, 19245865, 27014339, 27194394, 26202870, 27631816, 27696107, 27705013, 27313931, 28135145, 27829682, 17039270, 24728327, 28127763, 27783336, 28141798, 27870730, 25820570, 27153395, 26332594, 26822237, 26681312, 28687356, 28944238, 28503720, 25186627, 28577310, 29371908, 29766397, 28634180, 29785153, 28152038, 26556299, 29915346, 29406563, 29958926, 30067863, 30333958, 30609409, 30256826, 30702970, 30620386, 29978187, 30322717, 30309722, 30604180, 30833417, 31159747, 30676620, 31285513, 30877237, 31512090, 30306255, 32088803, 30291343, 28709830, 31618753, 31447099, 31263571, 32854451, 31980526, 33384714, 32338768, 33258288, 32830346, 33504652)

Comment:

The missense variant p.G396D in MUTYH (NM_001128425.2) has been observed in homozygous or compound heterozygous form with other pathogenic MUTYH variants in patients with adenomatous polyposis syndrome (Al-Tassan 2002, Ruggieri 2013). Functional characterization of the variant protein indicates a partial reduction in DNA binding and glycosylase activity (Ruggieri 2013). The observed variant has been reported in ClinVar as Pathogenic. The p.G396D variant is observed in 555/1,12,884 (0.4917%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and in 9/1,006 (0.8946%) alleles from individuals of European background in 1000 Genomes, which is greater than expected for the disorder. There is a moderate physicochemical difference between glycine and aspartic acid. The p.G396D missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.1187 in MUTYH is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.

Comment:

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 15987719; 18534194; 20848659; 23108399) - PS3_moderate. The c.1187G>A;p.(Gly396Asp)The c.1187G>A;p.(Gly396Asp) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 5294; PMID: 23035301; PMID: 19394335; PMID: 21171015; PMID: 24444654; PMID: 15931596) - PS4. The variant co-segregated with disease in multiple affected family members (PMID: 11818965, 16557584, 17489848) - PP1_strong. In summary, the currently available evidence indicates that the variant is pathogenic.

Comment:

The MUTYH c.1187G>A (p.Gly396Asp) missense change is a well-established pathogenic variant for MUTYH-associated polyposis and is estimated to account for up to 80% of cases in European patients (PMID: 23035301). Although MUTYH-associated polyposis is typically caused by biallelic variants affecting the MUTYH gene, there is evidence that monoallelic pathogenic MUTYH variants including this particular variant are associated with increased risk of colon cancer (PMID: 16492921, 19394335, 21171015, 24444654, 15931596). This variant has a maximum subpopulation frequency of 0.49% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, and functional studies have shown that this missense change disrupts MUTYH protein function (PMID: 15987719, 18534194, 20848659, 23108399). This variant has been reported to co-segregate with disease in individuals affected with colorectal cancer and polyposis (with polyp numbers ranging from 10 to >100) (PMID: 11818965, 16557584, 17489848, 19793053). In summary, this variant meets criteria to be classified as pathogenic.

Comment:

The MUTYH c.1187G>A; p.Gly396Asp variant (rs36053993; also known as NM_001048171.1: c.1145G>A; p.Gly382Asp) has been well described in the literature as one of the two common MUTYH pathogenic variants. It has been observed in homozygous or compound heterozygous form with other pathogenic MUTYH variants in patients with adenomatous polyposis syndrome (Al-Tassan 2002, Nielsen 2009, Ruggieri 2013), and is enriched in patients with an odds ratio of 6.47 (Theodoratou 2010). Functional characterization of the variant protein indicates a partial reduction in DNA binding and glycosylase activity (Ali 2008, D'Agostino 2010, Goto 2010, Komine 2015, Kundu 2009, Molatore 2010, Ruggieri 2013). Based on available information, this variant is considered to be pathogenic. References: Ali M et al. Characterization of mutant MUTYH proteins associated with familial colorectal cancer. Gastroenterology. 2008 135(2):499-507. PMID: 18534194. Al-Tassan N et al. Inherited variants of MYH associated with somatic G:C-->T:A mutations in colorectal tumors. Nat Genet. 2002 30(2):227-32. PMID: 11818965 D'Agostino V et al. Functional analysis of MUTYH mutated proteins associated with familial adenomatous polyposis. DNA Repair (Amst). 2010 9(6):700-7. PMID: 20418187. Goto M et al. Adenine DNA glycosylase activity of 14 human MutY homolog (MUTYH) variant proteins found in patients with colorectal polyposis and cancer. Hum Mutat. 2010 31(11):E1861-74. PMID: 20848659. Komine K et al. Functional Complementation Assay for 47 MUTYH Variants in a MutY-Disrupted Escherichia coli Strain. Hum Mutat. 2015 36(7):704-11. PMID: 25820570. Kundu S et al. Adenine removal activity and bacterial complementation with the human MutY homologue (MUTYH) and Y165C, G382D, P391L and Q324R variants associated with colorectal cancer. DNA Repair (Amst). 2009 8(12):1400-10. PMID: 19836313. Molatore S et al. MUTYH mutations associated with familial adenomatous polyposis: functional characterization by a mammalian cell-based assay. Hum Mutat. 2010 31(2):159-66. PMID: 19953527. Nielsen M et al. Analysis of MUTYH genotypes and colorectal phenotypes in patients With MUTYH-associated polyposis. Gastroenterology. 2009 136(2):471-6. PMID: 19032956. Ruggieri V et al. Loss of MUTYH function in human cells leads to accumulation of oxidative damage and genetic instability. Oncogene. 2013 32(38):4500-8. PMID: 23108399. Theodoratou E et al. A large-scale meta-analysis to refine colorectal cancer risk estimates associated with MUTYH variants. Br J Cancer. 2010 Dec 7;103(12):1875-84. PMID: 21063410.

Comment:

(p.Gly396Asp). This variant is present in population databases (rs36053993, gnomAD 0.5%), including at least one homozygous and/or hemizygous individual. This variant is a known common cause of MUTYH-associated polyposis (PMID: 23035301). This variant has been reported to co-segregate with disease in individuals affected with colorectal cancer and polyposis (with polyp numbers ranging from 10 to >100) (PMID: 11818965, 16557584, 17489848, 19793053). MUTYH-related conditions are inherited in an autosomal recessive fashion. However, there is evidence that monoallelic pathogenic MUTYH variants including this particular variant associated with increased risk of colon cancer (PMID: 16492921, 19394335, 21171015, 24444654, 15931596). This variant is also known as c.1145G>A (p.Gly382Asp). ClinVar contains an entry for this variant (Variation ID: 5294). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PoIyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MUTYH function (PMID: 15987719, 18534194, 20848659, 23108399). For these reasons, this variant has been classified as Pathogenic. Pathogcnic/likely pathogenic mutations in the MUTYH gene are associated with familial polyposis syndrome.

Comment:

This missense variant replaces glycine with aspartic acid at codon 396 of the MUTYH protein. This variant is also known as p.Gly382Asp (c.1145G>A) based on an alternate transcript NM_001048171. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). Functional studies have shown that the mutant protein exhibits significantly reduced activity in in vitro DNA glycosylase activity assay (PMID: 15036665, 15987719, 20848659). This variant is a well-established pathogenic variant known to cause adenomatous polyposis and colorectal cancer in homozygous or compound heterozygous individuals (PMID: 11818965, 12606733, 15635083, 16557584, 23361220, 25590978, 27783336, 28135145, 29147111). This variant is one of two most common pathogenic MUTYH variants, which together account for up to 80% of MUTYH-associated disease observed in Caucasian individuals (PMID: 29147111). This variant has been identified in 860/281146 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

Comment:

The c.1187G>A (p.G396D) alteration is located in coding exon 13 of the MUTYH gene. This alteration results from a G to A substitution at nucleotide position 1187, causing the glycine (G) at amino acid position 396 to be replaced by an aspartic acid (D). Based on data from gnomAD, the A allele has an overall frequency of 0.306% (860/281146) total alleles studied. The highest observed frequency was 0.489% (628/128314) of European (non-Finnish) alleles. This mutation has been identified in a significant percentage of individuals with MUTYH-associated polyposis and represents a founder mutation in multiple populations (Nielsen, 2009). Of the 12 individuals reported as p.G396D homozygotes by these authors, the mean age at clinical presentation was 51 years (range of 36-62). Nine of these 12 individuals had a history of colorectal cancer with a mean age at diagnosis of 58 years (range of 37-70). This amino acid position is highly conserved in available vertebrate species. Functional analysis demonstrated that the p.G396D alteration does not affect protein expression or splicing, but results in significantly reduced oxidative DNA mismatch repair efficiency compared to wild type (Plotz, 2012; Raetz, 2012; Ruggieri, 2013). RNA studies have demonstrated this alteration does not result in abnormal splicing in the set of samples tested (Ambry internal data). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

Comment:

The MUTYH c.1187G>A variant is predicted to result in the amino acid substitution p.Gly396Asp. This variant, alternatively described as “G382D or Gly382Asp”, is one of the most common pathogenic variants in MUTYH-associated polyposis (MAP) (Plotz et al. 2012. PubMed ID: 22473953; Olfson et al. 2015. PubMed ID: 26332594; Fabišíková et al. 2020. PubMed ID: 33384714; Daans et al. 2020. PubMed ID: 32088803; Curia et al. 2020. PubMed ID: 32821650). Functional (in vitro) studies of this variant have shown that it negatively affects protein function (Al-Tassan et al. 2002. PubMed ID: 11818965; Goto et al. 2010. PubMed ID: 20848659). However, this variant has been reported with a subpopulation frequency up to ~0.5%, including three homozygotes, in gnomAD. In ClinVar, the vast majority of clinical laboratories have classified this variant as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/5294/). Based on the collective evidence, we interpret this variant as pathogenic.

Comment:

This variant has been previously reported as disease-causing. It would be pathogenic in a recessive state; heterozygotes would be carriers for the condition. It was found once in our study heterozygous in a 6-year-old male with anaplastic ganglioglioma.

Comment:

The p.Gly396Asp variant was identified in 102 of 1112 proband chromosomes (frequency: 0.092) from individuals or families with colorectal cancer or MUTYH-associated polyposis, and was not identified in 264 control chromosomes from healthy individuals (Eliason 2006, Nielsen 2009, Sieber 2003). The p.Gly396Asp variant was also identified by our laboratory in 22 individuals with colorectal cancer or polyposis. The p.Gly396Asp variant was identified in dbSNP (ID:rs36053993 ) â€šÃ„ÃºWith pathogenic alleleâ€šÃ„Ã¹, with a minor allele frequency of 0.004 (1000 Genomes Project ), NHLBI Exome Sequencing Project (Exome Variant Server) in 50 of 13006 alleles (frequency: 0.004), HGMD, the â€šÃ„ÃºInSiGHT Colon Cancer Databaseâ€šÃ„Ã¹, and UMD (518X as a causal variant; co-occurring with 14 different pathogenic variants). The p.Gly396Asp variant was classified as a pathogenic variant by multiple submitters to the ClinVar database, including OMIM, GeneReviews, and Emory Genetics. The p.Gly396Asp variant occurs in the first base of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing and in-silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a significant difference in splicing. The p.Gly396 residue is conserved across mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Gly396Asp variant may impact the protein. In vitro assays using synthetic DNA substrates showed that the variant protein reduced adenine removal activity as compared to the wild-type protein and was partially active in DNA binding, base excision repair (BER) and glycosylase activities (Ali 2008, D'Agostino 2010). Two bacterial or mammalian cell-based studies by Kundu (2009) and Molatare (2009) found that the glycosylase activity of the p.Gly396Asp variant did not differ significantly from wild-type; however, Kundu (2009) suggests that the activity of the variant may be more reduced in human cells. Nielsen (2009) identified that although the phenotypic effects of the variant are relatively mild, there is a significantly greater colorectal cancer hazard for patients who were compound heterozygotes for this and a variant with truncating or certain other missense mutations. In summary, based on the above information, this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic

Comment:

Variant reported in multiple Invitae PIN participants by multiple clinical testing laboratories. Variant interpreted as Pathogenic by all laboratories and reported most recently on 10/09/20 by Invitae and 11/4/14 by Ambry Genetics GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant.

Comment:

Common pathogenic variants carried by approximately 1%-2% of the general population that account for ≥90% of all MUTYH pathogenic variants in northern European populations; ≤70% of persons with MUTYH-Associated Polyposis (MAP) harbor at least 1 of these variants, 536A>G or 1187G>A

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Actionable secondary findings following exome sequencing of 836 non-obstructive azoospermia cases and their value in patient management.	Kasak L	Human reproduction (Oxford, England)	2022	PMID: 35535697
Germline Alterations in Patients With IBD-associated Colorectal Cancer.	Biscaglia G	Inflammatory bowel diseases	2022	PMID: 34347074
The genetic structure of the Turkish population reveals high levels of variation and admixture.	Kars ME	Proceedings of the National Academy of Sciences of the United States of America	2021	PMID: 34426522
Prospective pan-cancer germline testing using MSK-IMPACT informs clinical translation in 751 patients with pediatric solid tumors.	Fiala EM	Nature cancer	2021	PMID: 34308366
Exome sequencing of familial adenomatous polyposis-like individuals identifies both known and novel causative genes.	Xavier A	Clinical genetics	2021	PMID: 34259353
Whole-exome sequencing reveals germline-mutated small cell lung cancer subtype with favorable response to DNA repair-targeted therapies.	Tlemsani C	Science translational medicine	2021	PMID: 33504652
Prevalence of pathogenic germline variants in patients with metastatic renal cell carcinoma.	Santos M	Genetics in medicine : official journal of the American College of Medical Genetics	2021	PMID: 33442023
Pathogenic germline variants in patients with features of hereditary renal cell carcinoma: Evidence for further locus heterogeneity.	Smith PS	Genes, chromosomes & cancer	2021	PMID: 32830346
MUTYH Polyposis.	Adam MP	-	2021	PMID: 23035301
Case Report: The Role of Molecular Analysis of the MUTYH Gene in Asymptomatic Individuals.	Fabišíková K	Frontiers in genetics	2020	PMID: 33384714
Diagnostic power and clinical impact of exome sequencing in a cohort of 500 patients with rare diseases.	Quaio CRDC	American journal of medical genetics. Part C, Seminars in medical genetics	2020	PMID: 33258288
Exome sequencing and characterization of 49,960 individuals in the UK Biobank.	Van Hout CV	Nature	2020	PMID: 33087929
Detection of Germline Mutations in a Cohort of 139 Patients with Bilateral Breast Cancer by Multi-Gene Panel Testing: Impact of Pathogenic Variants in Other Genes beyond BRCA1/2.	Fanale D	Cancers	2020	PMID: 32854451
Rare Tumor-Normal Matched Whole Exome Sequencing Identifies Novel Genomic Pathogenic Germline and Somatic Aberrations.	Sprissler R	Cancers	2020	PMID: 32570879
Rare germline genetic variants and risk of aggressive prostate cancer.	Nguyen-Dumont T	International journal of cancer	2020	PMID: 32338768
Actionable Exomic Secondary Findings in 280 Lebanese Participants.	Jalkh N	Frontiers in genetics	2020	PMID: 32231684
Increased prevalence of Barrett's esophagus in patients with MUTYH-associated polyposis (MAP).	Daans CG	Familial cancer	2020	PMID: 32088803
Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging.	Hou YC	Proceedings of the National Academy of Sciences of the United States of America	2020	PMID: 31980526
Genotype-phenotype analysis of 523 patients by genetics evaluation and clinical exome sequencing.	Ziats MN	Pediatric research	2020	PMID: 31618753
Germline investigation in male breast cancer of DNA repair genes by next-generation sequencing.	Scarpitta R	Breast cancer research and treatment	2019	PMID: 31512090
Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network.	eMERGE Consortium. Electronic address: [email protected]	American journal of human genetics	2019	PMID: 31447099
Contribution of New Adenomatous Polyposis Predisposition Genes in an Unexplained Attenuated Spanish Cohort by Multigene Panel Testing.	Lorca V	Scientific reports	2019	PMID: 31285513
High frequency of pathogenic germline variants within homologous recombination repair in patients with advanced cancer.	Bertelsen B	NPJ genomic medicine	2019	PMID: 31263571
Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations.	Tsaousis GN	BMC cancer	2019	PMID: 31159747
Clinical characteristics of patients with colorectal cancer with double somatic mismatch repair mutations compared with Lynch syndrome.	Pearlman R	Journal of medical genetics	2019	PMID: 30877237
Base excision repair deficiency signatures implicate germline and somatic MUTYH aberrations in pancreatic ductal adenocarcinoma and breast cancer oncogenesis.	Thibodeau ML	Cold Spring Harbor molecular case studies	2019	PMID: 30833417
Comprehensive Paired Tumor/Germline Testing for Lynch Syndrome: Bringing Resolution to the Diagnostic Process.	Salvador MU	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2019	PMID: 30702970
Association of Inherited Pathogenic Variants in Checkpoint Kinase 2 (CHEK2) With Susceptibility to Testicular Germ Cell Tumors.	AlDubayan SH	JAMA oncology	2019	PMID: 30676620
Ampullary cancer: Evaluation of somatic and germline genetic alterations and association with clinical outcomes.	Wong W	Cancer	2019	PMID: 30620386
Interpretation of Genomic Sequencing Results in Healthy and Ill Newborns: Results from the BabySeq Project.	Ceyhan-Birsoy O	American journal of human genetics	2019	PMID: 30609409
Multi-gene panel testing confirms phenotypic variability in MUTYH-Associated Polyposis.	Sutcliffe EG	Familial cancer	2019	PMID: 30604180
Monoallelic MUTYH carrier status is not associated with increased breast cancer risk in a multigene panel cohort.	Fulk K	Familial cancer	2019	PMID: 30582135
1 in 38 individuals at risk of a dominant medically actionable disease.	Haer-Wigman L	European journal of human genetics : EJHG	2019	PMID: 30291343
The Ethnic-Specific Spectrum of Germline Nucleotide Variants in DNA Damage Response and Repair Genes in Hereditary Breast and Ovarian Cancer Patients of Tatar Descent.	Brovkina OI	Frontiers in oncology	2018	PMID: 30333958
Germline pathogenic variants identified in women with ovarian tumors.	Carter NJ	Gynecologic oncology	2018	PMID: 30322717
Patients with BRCA mutations have superior outcomes after intraperitoneal chemotherapy in optimally resected high grade ovarian cancer.	Naumann RW	Gynecologic oncology	2018	PMID: 30309722
Multigene panel testing beyond BRCA1/2 in breast/ovarian cancer Spanish families and clinical actionability of findings.	Bonache S	Journal of cancer research and clinical oncology	2018	PMID: 30306255
Novel genetic mutations detected by multigene panel are associated with hereditary colorectal cancer predisposition.	Martin-Morales L	PloS one	2018	PMID: 30256826
Prospective study of germline genetic testing in incident cases of pancreatic adenocarcinoma.	Brand R	Cancer	2018	PMID: 30067863
Prevalence of Germline Mutations in Cancer Susceptibility Genes in Patients With Advanced Renal Cell Carcinoma.	Carlo MI	JAMA oncology	2018	PMID: 29978187
Prevalence of deleterious mutations among patients with breast cancer referred for multigene panel testing in a Romanian population.	Goidescu IG	Clujul medical (1957)	2018	PMID: 29785153
Novel variant of unknown significance in MUTYH in a patient with MUTYH-associated polyposis: a case to reclassify.	Kidambi TD	Clinical journal of gastroenterology	2018	PMID: 29766397
Genetic variants of prospectively demonstrated phenocopies in BRCA1/2 kindreds.	Dominguez-Valentin M	Hereditary cancer in clinical practice	2018	PMID: 29371908
Hereditary Colorectal Tumors: A Literature Review on MUTYH-Associated Polyposis.	Kantor M	Gastroenterology research and practice	2017	PMID: 29147111
Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes.	DeRycke MS	Molecular genetics & genomic medicine	2017	PMID: 28944238
Pathologic findings in breast, fallopian tube, and ovary specimens in non-BRCA hereditary breast and/or ovarian cancer syndromes: a study of 18 patients with deleterious germline mutations in RAD51C, BARD1, BRIP1, PALB2, MUTYH, or CHEK2.	Schoolmeester JK	Human pathology	2017	PMID: 28709830
Germline mutations in DNA repair genes predispose asbestos-exposed patients to malignant pleural mesothelioma.	Betti M	Cancer letters	2017	PMID: 28687356
A MUTYH germline mutation is associated with small intestinal neuroendocrine tumors.	Dumanski JP	Endocrine-related cancer	2017	PMID: 28634180
Elucidating the molecular basis of MSH2-deficient tumors by combined germline and somatic analysis.	Vargas-Parra GM	International journal of cancer	2017	PMID: 28577310
Contribution of germline mutations in cancer predisposition genes to tumor etiology in young women diagnosed with invasive breast cancer.	Rummel SK	Breast cancer research and treatment	2017	PMID: 28503720
Use of multigene-panel identifies pathogenic variants in several CRC-predisposing genes in patients previously tested for Lynch Syndrome.	Hansen MF	Clinical genetics	2017	PMID: 28195393
Exome sequencing covers >98% of mutations identified on targeted next generation sequencing panels.	LaDuca H	PloS one	2017	PMID: 28152038
Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer.	Yurgelun MB	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2017	PMID: 28135145
Mutational signature analysis identifies MUTYH deficiency in colorectal cancers and adrenocortical carcinomas.	Pilati C	The Journal of pathology	2017	PMID: 28127763
Type and frequency of MUTYH variants in Italian patients with suspected MAP: a retrospective multicenter study.	Ricci MT	Journal of human genetics	2017	PMID: 27829682
Attenuated polyposis of the large bowel: a morphologic and molecular approach.	de Leon MP	Familial cancer	2017	PMID: 27783336
Cutaneous Sebaceous Lesions in a Patient With MUTYH-Associated Polyposis Mimicking Muir-Torre Syndrome.	Kacerovska D	The American Journal of dermatopathology	2016	PMID: 27870730
Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer.	Maxwell KN	American journal of human genetics	2016	PMID: 27153395
An Individual with Both MUTYH-Associated Polyposis and Lynch Syndrome Identified by Multi-Gene Hereditary Cancer Panel Testing: A Case Report.	Cohen SA	Frontiers in genetics	2016	PMID: 27014339
Diagnostic Yield of Clinical Tumor and Germline Whole-Exome Sequencing for Children With Solid Tumors.	Parsons DW	JAMA oncology	2016	PMID: 26822237
Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing.	Susswein LR	Genetics in medicine : official journal of the American College of Medical Genetics	2016	PMID: 26681312
Germline Variants in Targeted Tumor Sequencing Using Matched Normal DNA.	Schrader KA	JAMA oncology	2016	PMID: 26556299
Identification of Medically Actionable Secondary Findings in the 1000 Genomes.	Olfson E	PloS one	2015	PMID: 26332594
Risk of colorectal cancer for people with a mutation in both a MUTYH and a DNA mismatch repair gene.	Win AK	Familial cancer	2015	PMID: 26202870
Functional Complementation Assay for 47 MUTYH Variants in a MutY-Disrupted Escherichia coli Strain.	Komine K	Human mutation	2015	PMID: 25820570
Racial variation in frequency and phenotypes of APC and MUTYH mutations in 6,169 individuals undergoing genetic testing.	Inra JA	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25590978
Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel.	Tung N	Cancer	2015	PMID: 25186627
Prevalence of germline MUTYH mutations among Lynch-like syndrome patients.	Castillejo A	European journal of cancer (Oxford, England : 1990)	2014	PMID: 24953332
Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing.	Bodian DL	PloS one	2014	PMID: 24728327
Risk of colorectal cancer for carriers of mutations in MUTYH, with and without a family history of cancer.	Win AK	Gastroenterology	2014	PMID: 24444654
MUTYH-associated polyposis (MAP): evidence for the origin of the common European mutations p.Tyr179Cys and p.Gly396Asp by founder events.	Aretz S	European journal of human genetics : EJHG	2014	PMID: 23361220
Integrative analysis of hereditary nonpolyposis colorectal cancer: the contribution of allele-specific expression and other assays to diagnostic algorithms.	De Lellis L	PloS one	2013	PMID: 24278394
Personalized genomic disease risk of volunteers.	Gonzalez-Garay ML	Proceedings of the National Academy of Sciences of the United States of America	2013	PMID: 24082139
Germline Mutations in the Polyposis-Associated Genes BMPR1A, SMAD4, PTEN, MUTYH and GREM1 Are Not Common in Individuals with Serrated Polyposis Syndrome.	Clendenning M	PloS one	2013	PMID: 23805267
Colorectal cancer in a monoallelic MYH mutation carrier.	Khalaf R	Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract	2013	PMID: 23625202
Loss of MUTYH function in human cells leads to accumulation of oxidative damage and genetic instability.	Ruggieri V	Oncogene	2013	PMID: 23108399
Cancer-associated variants and a common polymorphism of MUTYH exhibit reduced repair of oxidative DNA damage using a GFP-based assay in mammalian cells.	Raetz AG	Carcinogenesis	2012	PMID: 22926731
High prevalence of the c.1227_1228dup (p.Glu410GlyfsX43) mutation in Tunisian families affected with MUTYH-associated-polyposis.	Abdelmaksoud-Dammak R	Familial cancer	2012	PMID: 22744763
Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes.	Johnston JJ	American journal of human genetics	2012	PMID: 22703879
MUTYH gene expression and alternative splicing in controls and polyposis patients.	Plotz G	Human mutation	2012	PMID: 22473953
MUTYH gene variants and breast cancer in a Dutch case–control study.	Out AA	Breast cancer research and treatment	2012	PMID: 22297469
MutYH mutation carriers have increased breast cancer risk.	Rennert G	Cancer	2012	PMID: 21952991
MUTYH-associated colon disease: adenomatous polyposis is only one of the possible phenotypes. A family report and literature review.	Zorcolo L	Tumori	2011	PMID: 22158503
First large rearrangement in the MUTYH gene and attenuated familial adenomatous polyposis syndrome.	Rouleau E	Clinical genetics	2011	PMID: 21815886
Cancer risks for monoallelic MUTYH mutation carriers with a family history of colorectal cancer.	Win AK	International journal of cancer	2011	PMID: 21171015
Rectum-sparing surgery may be appropriate for biallelic MutYH-associated polyposis.	Nascimbeni R	Diseases of the colon and rectum	2010	PMID: 21178863
A large-scale meta-analysis to refine colorectal cancer risk estimates associated with MUTYH variants.	Theodoratou E	British journal of cancer	2010	PMID: 21063410
Adenine DNA glycosylase activity of 14 human MutY homolog (MUTYH) variant proteins found in patients with colorectal polyposis and cancer.	Goto M	Human mutation	2010	PMID: 20848659
MUTYH-associated polyposis - variability of the clinical phenotype in patients with biallelic and monoallelic MUTYH mutations and report on novel mutations.	Morak M	Clinical genetics	2010	PMID: 20618354
Functional analysis of MUTYH mutated proteins associated with familial adenomatous polyposis.	D'Agostino VG	DNA repair	2010	PMID: 20418187
Biallelic MYH germline mutations as cause of Muir-Torre syndrome.	Guillén-Ponce C	Familial cancer	2010	PMID: 19998059
MUTYH mutations associated with familial adenomatous polyposis: functional characterization by a mammalian cell-based assay.	Molatore S	Human mutation	2010	PMID: 19953527
Adenine removal activity and bacterial complementation with the human MutY homologue (MUTYH) and Y165C, G382D, P391L and Q324R variants associated with colorectal cancer.	Kundu S	DNA repair	2009	PMID: 19836313
APC or MUTYH mutations account for the majority of clinically well-characterized families with FAP and AFAP phenotype and patients with more than 30 adenomas.	Filipe B	Clinical genetics	2009	PMID: 19793053
Expanded extracolonic tumor spectrum in MUTYH-associated polyposis.	Vogt S	Gastroenterology	2009	PMID: 19732775
Clinical implications of the colorectal cancer risk associated with MUTYH mutation.	Lubbe SJ	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2009	PMID: 19620482
Increased colorectal cancer incidence in obligate carriers of heterozygous mutations in MUTYH.	Jones N	Gastroenterology	2009	PMID: 19394335
Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study.	Cleary SP	Gastroenterology	2009	PMID: 19245865
Analysis of MUTYH genotypes and colorectal phenotypes in patients With MUTYH-associated polyposis.	Nielsen M	Gastroenterology	2009	PMID: 19032956
Characterization of mutant MUTYH proteins associated with familial colorectal cancer.	Ali M	Gastroenterology	2008	PMID: 18534194
Germline mutation prevalence in the base excision repair gene, MYH, in patients with endometrial cancer.	Barnetson RA	Clinical genetics	2007	PMID: 17956577
Germline mutations in APC and MUTYH are responsible for the majority of families with attenuated familial adenomatous polyposis.	Nielsen M	Clinical genetics	2007	PMID: 17489848
MUTYH-associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype.	Aretz S	International journal of cancer	2006	PMID: 16557584
Risk of colorectal cancer in monoallelic and biallelic carriers of MYH mutations: a population-based case-family study.	Jenkins MA	Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology	2006	PMID: 16492921
Cells with pathogenic biallelic mutations in the human MUTYH gene are defective in DNA damage binding and repair.	Parker AR	Carcinogenesis	2005	PMID: 15987719
Germline susceptibility to colorectal cancer due to base-excision repair gene defects.	Farrington SM	American journal of human genetics	2005	PMID: 15931596
The potential for increased clinical sensitivity in genetic testing for polyposis colorectal cancer through the analysis of MYH mutations in North American patients.	Eliason K	Journal of medical genetics	2005	PMID: 15635083
Identification of critical residues required for the mutation avoidance function of human MutY (hMYH) and implications in colorectal cancer.	Wooden SH	Cancer letters	2004	PMID: 15036665
Mutator phenotype of MUTYH-null mouse embryonic stem cells.	Hirano S	The Journal of biological chemistry	2003	PMID: 12917422
Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH.	Sieber OM	The New England journal of medicine	2003	PMID: 12606733
Inherited variants of MYH associated with somatic G:C-->T:A mutations in colorectal tumors.	Al-Tassan N	Nature genetics	2002	PMID: 11818965
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MUTYH	-	-	-	-
click to load more click to collapse

Text-mined citations for rs36053993 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_001048174.2(MUTYH):c.1103G>A (p.Gly368Asp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs36053993 ...