VCV000089357.110 - ClinVar

NM_000179.3(MSH6):c.3226C>T (p.Arg1076Cys)

Germline

Top reviewed classifications are shown here.

Submission summary:

29 submissions

29 submitters

14 conditions

Reviewed by expert panel

Likely pathogenic

Mar 2018 by International …

for Lynch syndrome 1

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000179.3(MSH6):c.3226C>T (p.Arg1076Cys)

Variation ID: 89357 Accession: VCV000089357.110

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p16.3 2: 47803473 (GRCh38) [ NCBI UCSC ] 2: 48030612 (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	Oct 9, 2016	Nov 24, 2024	Mar 9, 2018

HGVS

Nucleotide	Protein	Molecular consequence
NM_000179.3:c.3226C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000170.1:p.Arg1076Cys	missense
NM_001281492.2:c.2836C>T	NP_001268421.1:p.Arg946Cys	missense
NM_001281493.2:c.2320C>T	NP_001268422.1:p.Arg774Cys	missense
NM_001281494.2:c.2320C>T	NP_001268423.1:p.Arg774Cys	missense
NC_000002.12:g.47803473C>T
NC_000002.11:g.48030612C>T
NG_007111.1:g.25327C>T
LRG_219:g.25327C>T
LRG_219t1:c.3226C>T	LRG_219p1:p.Arg1076Cys
	P52701:p.Arg1076Cys

... more HGVS ... less HGVS

Protein change

R1076C, R774C, R946C

Other names

Canonical SPDI

NC_000002.12:47803472: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.

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

The Genome Aggregation Database (gnomAD) 0.00002

Links

ClinGen: CA012063 UniProtKB: P52701#VAR_043965 dbSNP: rs63750617 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.
MSH6		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	9164	9483

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.
Lynch syndrome 1	Likely pathogenic (3)	reviewed by expert panel	Mar 9, 2018	RCV000074823.13
Hereditary cancer-predisposing syndrome	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jul 6, 2023	RCV000162445.25
not provided	Pathogenic/Likely pathogenic (6)	criteria provided, multiple submitters, no conflicts	Aug 9, 2024	RCV000254700.48
Hereditary nonpolyposis colorectal neoplasms	Pathogenic (1)	criteria provided, single submitter	Jan 31, 2024	RCV000524159.18
Lynch syndrome 5	Likely pathogenic (6)	criteria provided, multiple submitters, no conflicts	Oct 4, 2021	RCV000709742.16
Hereditary nonpolyposis colon cancer	Likely pathogenic (1)	criteria provided, single submitter	Jun 3, 2024	RCV000780464.14
Malignant tumor of breast	Likely pathogenic (1)	no assertion criteria provided	-	RCV001356266.10
Breast carcinoma	Likely pathogenic (1)	no assertion criteria provided	Aug 16, 2021	RCV001564011.9
Gastric cancer	Pathogenic (1)	no assertion criteria provided	Jul 1, 2021	RCV003162475.8
Inherited prostate cancer	Likely pathogenic (1)	criteria provided, single submitter	May 8, 2024	RCV004584185.1
Endometrial carcinoma	Likely pathogenic (1)	criteria provided, single submitter	Feb 24, 2024	RCV003466947.2
Breast and/or ovarian cancer	Likely pathogenic (1)	criteria provided, single submitter	Nov 9, 2022	RCV003492400.1
Lynch syndrome	Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 8, 2024	RCV003997086.2
MSH6-related disorder	Likely pathogenic (1)	no assertion criteria provided	Jul 23, 2024	RCV004739334.1
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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.
Likely pathogenic (Mar 09, 2018)	reviewed by expert panel (Guidelines v2.3) Method: curation	Lynch syndrome 1 Affected status: yes Allele origin: germline	International Society for Gastrointestinal Hereditary Tumours (InSiGHT) Accession: SCV000108034.3 First in ClinVar: Dec 19, 2013 Last updated: Apr 14, 2018	Other databases http://www.insight-database.org/… http://www.insight-database.org/classifications/?gene=MSH6&variant=c.3226C%3ET Comment: Co-occurrence in trans with a known pathogenic sequence variant in the same gene in a patient with clinical features consistent with CMMRD and documented MMR … (more) Co-occurrence in trans with a known pathogenic sequence variant in the same gene in a patient with clinical features consistent with CMMRD and documented MMR deficiency in normal cells (less)
Likely pathogenic (Nov 09, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast and/or ovarian cancer Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV004239315.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024
Pathogenic (Dec 13, 2021)	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: SCV000212797.10 First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024	Publications: PubMed (13) PubMed: 16418736‚ 16525781‚ 18409202‚ 21039432‚ 21056691‚ 21836479‚ 22250089‚ 22495361‚ 26832770‚ 27398995‚ 27696107‚ 29785566‚ 30521064 Comment: The p.R1076C pathogenic mutation (also known as c.3226C>T), located in coding exon 5 of the MSH6 gene, results from a C to T substitution at … (more) The p.R1076C pathogenic mutation (also known as c.3226C>T), located in coding exon 5 of the MSH6 gene, results from a C to T substitution at nucleotide position 3226. The arginine at codon 1076 is replaced by cysteine, an amino acid with highly dissimilar properties. The in silico prediction for this alteration is inconclusive and this amino acid position is highly conserved in available vertebrate species. In one study, the p.R1076C mutation was detected in a male proband with colorectal cancer (CRC) at age 55 and a previous diagnosis of gastric cancer. The colorectal tumor of the proband demonstrated clonal loss of expression of both MSH2 and MSH6 proteins by immunohistochemistry (IHC). In addition, this individual's family history included a brother with CRC, an aunt with ovarian cancer, and a cousin with endometrial cancer (Schofield L et al. Int. J .Cancer. 2009 Sep;125:1492-3). The p.R1076C mutation was also reported in a 46-year-old man diagnosed with ascending colon cancer, but his tumor IHC testing showed intact staining for the MLH1, MSH2, and MSH6 proteins (Limburg PJ et al. Clin. Gastroenterol. Hepatol. 2011 Jun;9:497-502). Furthermore, the p.R1076C mutation was identified in a proband with a microsatellite stable endometrial cancer with intact staining for the MLH1, MSH2, and MSH6 proteins on IHC (Rubio I et al. Oncology. 2016 Jul;91(3):171-6). In addition, this mutation has been identified in multiple individuals whose Lynch syndrome-associated tumors displayed high microsatellite instability and/or had isolated loss of MSH6 on immunohistochemistry (IHC); however, at least two probands had intact staining on IHC (Ambry internal data). At least five individuals with features of CMMR-D have been reported to carry the p.R1076C mutation and a pathogenic (nonsense/frameshift) MSH6 mutation in trans, suggesting biallelic mismatch repair inactivation (Plaschke J et al. Eur. J. Hum. Genet. 2006 May;14:561-6; Okkels H et al. Int. J. Colorectal Dis. 2006 Dec;21:847-50; Rahner N et al. Am. J. Med. Genet. A. 2008 May;146A:1314-9; Jasperson KW et al. Clin. Genet. 2011 Oct;80:394-7). However, an individual found to be homozygous for this mutation did not present with classic CMMR-D symptoms and instead developed CRC at the ages of 45 and 49, suggesting that this variant may be hypomorphic. As risk estimates are unknown at this time, clinical correlation is advised. Based on the total supporting evidence, this alteration is interpreted as a disease-causing mutation, but may represent a low- or lower-penetrance MSH6 allele with regards to CMMR-D. (less)
Likely pathogenic (Feb 24, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Endometrial carcinoma Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004197560.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Likely pathogenic (May 08, 2024)	criteria provided, single submitter (ACGS Best Practice Guidelines for Variant Classification in Rare Disease 2020) Method: clinical testing	Inherited prostate cancer Affected status: yes Allele origin: germline	Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service Accession: SCV005068349.1 First in ClinVar: Jul 07, 2024 Last updated: Jul 07, 2024	Comment: PM3_Strong,PP3,PP4_Moderate
Likely pathogenic (Jun 03, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Hereditary nonpolyposis colon cancer Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000917733.5 First in ClinVar: Jun 02, 2019 Last updated: Sep 16, 2024	Publications: PubMed (18) PubMed: 16418736‚ 21056691‚ 22949379‚ 23621914‚ 21836479‚ 16525781‚ 18409202‚ 19072991‚ 27696107‚ 27601186‚ 28481244‚ 22250089‚ 28514183‚ 34271781‚ 35884469‚ 34637943‚ 35725860‚ 36243179 Comment: Variant summary: MSH6 c.3226C>T (p.Arg1076Cys) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the … (more) Variant summary: MSH6 c.3226C>T (p.Arg1076Cys) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.5e-05 in 251346 control chromosomes (gnomAD). This frequency is lower than expected for a pathogenic variant in MSH6 causing Lynch Syndrome (9.5e-05 vs 0.00014), allowing no conclusion about variant significance. The variant, c.3226C>T, has been reported in compound heterozygous state with other pathogenic MSH6 truncating variants in several patients with constitutional mismatch repair deficiency (CMMRD) syndrome, i.e. early-onset colorectal cancer, adenomatous polyposis and cafe-au-lait spots (Okkels 2006, Plaschke 2006, Rahner 2008, Allred 2013). In many of these cases the loss of MSH6 staining in both the tumor and normal cells was described, pointing to a bi-allelic MSH6 mutation. The variant was also reported in heterozygosity in individuals affected by Lynch syndrome (Schofield 2009, Lagerstedt-Robinson 2016, Rohlin 2016, Liccardo 2017, Espenschied 2017, Kim_2022, Duzkale_2021), where in several cases the associated tumor demonstrated isolated loss of MSH6 staining. However, within the reported CMMRD families the variant was also observed in heterozygous state in unaffected family members (Plaschke 2006, Okkels 2006, Allred 2013), suggesting its role in causing Lynch syndrome is uncertain. This variant was also found in a homozygote who developed colorectal tumors at the age of 45 and 49 year, together with multiple colon adenomas and polyps (Gardes 2012), a disease history that is closer to Lynch syndrome than CMMRD. However, in LCLs derived from this patient, though MSH6 mRNA was detectable, Western blot analysis demonstrated the lack of MSH6 protein, a finding that is consistent with CMMRD (Gardes 2012). These data indicate that the variant may be a hypomorphic allele, though no functional studies are available to support this assumption. The following publications have been ascertained in the context of this evaluation (PMID: 34637943, 34271781, 28514183, 22250089, 35884469, 21836479, 27601186, 28481244, 21056691, 35725860, 36243179, 16525781, 16418736, 18409202, 27696107, 19072991, 23621914, 22949379, Allred_2013). ClinVar contains an entry for this variant (Variation ID: 89357). Based on the evidence outlined above, the variant was classified as likely pathogenic for constitutional mismatch repair deficiency (CMMRD) syndrome. (less)
Likely pathogenic (Aug 09, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000321908.13 First in ClinVar: Oct 09, 2016 Last updated: Nov 24, 2024	Comment: Observed in individuals with a personal and/or family history of colorectal cancer, some with tumor studies demonstrating loss of MSH6 protein expression (PMID: 18566915, 19072991, … (more) Observed in individuals with a personal and/or family history of colorectal cancer, some with tumor studies demonstrating loss of MSH6 protein expression (PMID: 18566915, 19072991, 21056691, 27398995, 26832770, 28481244, 27696107, 33194656); May be a hypomorphic allele as it was observed in the homozygous state in patients with relatively late onset colorectal cancer/CMMR-D, and, among heterozygotes, a limited number of Lynch-associated cancers have been observed in multiple internal and published families (PMID: 16525781, 18409202, 22250089, 38789506); 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: 22949379, 15483016, 20531397, 22886683, 32980694, 31830689, 34637943, 29922827, 28888541, 32832836, 32029870, 33194656, 17531815, 21120944, 23621914, 18566915, 21674763, 21056691, 16525781, 16418736, 18409202, 19072991, 21039432, 26832770, 24012250, 27398995, 22250089, 18709565, 27601186, 27696107, 29785566, 28481244, 21836479, 22495361, 21376568, 30521064, 30322717, 32635641, 31721094, 31997046, 31447099, 32658311, 33422121, 31589614, 33309985, 37306523, 35861108, 36744932, 31391288, 36243179, 37175550, 34308104, 34873480, 35725860, 32719484, 30787465, 33087929, 32427313, 34445333, 33365374, 35535697, 37728764, 30608896, 38789506) (less)
Likely pathogenic (Oct 15, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 5 Affected status: unknown Allele origin: germline	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine Accession: SCV000840015.1 First in ClinVar: Oct 14, 2018 Last updated: Oct 14, 2018	Comment: This c.3226C>T (p.Arg1076Cys) variant in the MSH6 gene has been reported in the homozygous state in 1 individual with colorectal cancer (PMID: 22250089). It has … (more) This c.3226C>T (p.Arg1076Cys) variant in the MSH6 gene has been reported in the homozygous state in 1 individual with colorectal cancer (PMID: 22250089). It has also been reported in trans configuration with a pathogenic variant in 3 unrelated individuals with autosomal recessive hereditary nonpolyposis colorectal cancer type 5 (HNPCC5; PMID: 16418736, 16525781, 18409202) and in 2 related individuals with mismatch repair cancer syndrome (MMRCS; MIM 600678; PMID: 21039432). Segregation studies in this family confirmed that the c.3226C>T (p.Arg1076Cys) variant segregated together with a second pathogenic variant in the 2 affected individuals, but not in 6 unaffected family members (PMID: 21039432). The c.3226C>T variant is very rare in the general population. While not validated for clinical use, the computer-based algorithms PolyPhen-2 and SIFT predict the p.Arg1076Cys change to be deleterious. Based on this information, the c.3226C>T (p.Arg1076Cys) variant in the MSH6 gene is classified as likely pathogenic. (less)
Likely pathogenic (Sep 11, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Lynch syndrome 5 Affected status: unknown Allele origin: unknown	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology Study: AGHI_GT Accession: SCV000993566.1 First in ClinVar: Sep 25, 2019 Last updated: Sep 25, 2019	Observation 1: Number of individuals with the variant: 1 Observation 2: Number of individuals with the variant: 1
Likely pathogenic (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Lynch syndrome 5 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001135834.1 First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020
Likely pathogenic (Apr 02, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 1 Affected status: yes Allele origin: germline	Department of Molecular Diagnostics, Institute of Oncology Ljubljana Accession: SCV001499739.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021
Likely pathogenic (Oct 04, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 5 Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001976432.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Likely pathogenic (Dec 24, 2020)	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: SCV002049397.1 First in ClinVar: Jan 08, 2022 Last updated: Jan 08, 2022	Comment: The MSH6 c.3226C>T; p.Arg1076Cys variant (rs63750617) is reported in the literature in multiple heterozygous individuals affected with Lynch syndrome (Lagerstedt-Robinson 2016, Liccardo 2017, Schofield 2009). … (more) The MSH6 c.3226C>T; p.Arg1076Cys variant (rs63750617) is reported in the literature in multiple heterozygous individuals affected with Lynch syndrome (Lagerstedt-Robinson 2016, Liccardo 2017, Schofield 2009). This variant has also been reported in trans to another pathogenic variant in multiple individuals with symptoms consistent with constitutional mismatch repair deficiency (CMMRD) syndrome (Gardes 2012, Jasperson 2011, Okkels 2006, Plaschke 2006). However, the p.Arg1076Cys variant has also been found in a homozygous individual with symptoms more consistent with Lynch syndrome (Gardes 2012), as well as in healthy heterozygous relatives of affected individuals (Jasperson 2011, Okkels 2006, Plaschke 2006), suggesting it may exhibit incomplete penetrance. This variant is found in the general population with a low overall allele frequency of 0.01% (24/251346 alleles) in the Genome Aggregation Database. The arginine at codon 1076 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.849). Patient cells carrying this variant exhibit reduced resolution of irradiation-induced DNA damage foci compared to control cells (Gardes 2012), suggesting reduced DNA damage repair activity. Based on available information, this variant is considered to be likely pathogenic. References: Gardes P et al. Human MSH6 deficiency is associated with impaired antibody maturation. J Immunol. 2012 Feb 15;188(4):2023-9. Jasperson KW et al. Constitutional mismatch repair-deficiency syndrome presenting as colonic adenomatous polyposis: clues from the skin. Clin Genet. 2011 Oct;80(4):394-7. Lagerstedt-Robinson K et al. Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population. Oncol Rep. 2016 Nov;36(5):2823-2835. Liccardo R, De Rosa M, Rossi GB, Carlomagno N, Izzo P, Duraturo F. Incomplete Segregation of MSH6 Frameshift Variants with Phenotype of Lynch Syndrome. Int J Mol Sci. 2017 May 6;18(5):999. Okkels H et al. Polyposis and early cancer in a patient with low penetrant mutations in MSH6 and APC: hereditary colorectal cancer as a polygenic trait. Int J Colorectal Dis. 2006 Dec;21(8):847-50. Plaschke J et al. Compound heterozygosity for two MSH6 mutations in a patient with early onset of HNPCC-associated cancers, but without hematological malignancy and brain tumor. Eur J Hum Genet. 2006 May;14(5):561-6. Schofield L et al. Population-based detection of Lynch syndrome in young colorectal cancer patients using microsatellite instability as the initial test. Int J Cancer. 2009 Mar 1;124(5):1097-102. (less)
Likely pathogenic (Apr 13, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002527986.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The MSH6 c.3226C>T (p.R1076C) variant has been reported as compound heterozygous with other MSH6 pathogenic variants in 5 individuals with autosomal recessive constitutional mismatch repair … (more) The MSH6 c.3226C>T (p.R1076C) variant has been reported as compound heterozygous with other MSH6 pathogenic variants in 5 individuals with autosomal recessive constitutional mismatch repair deficiency (CMMR-D) syndrome (PMID: 16418736, 16525781, 18409202, 21039432). An individual homozygous for this variant did not present with CMMR-D, but did develop colorectal tumors at age of 45 (PMID: 22250089). It has also been reported in 2 individuals with colon cancer (PMID: 21056691, 27696107). Tumors found in these patients exhibit loss of MSH6 protein expression (PMID: 16525781, 22250089). Computational analyses and evolutionary conservation suggest that the variant does impact the function of protein, though these predictions have not been confirmed by published functional studies. This variant has been observed in 24/251346 chromosomes in the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). Based on the current evidence available, this variant is interpreted as likely pathogenic. (less)	Publications: PubMed (7) PubMed: 16418736‚ 16525781‚ 18409202‚ 21039432‚ 22250089‚ 21056691‚ 27696107
Likely pathogenic (May 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Lynch syndrome 1 Affected status: unknown Allele origin: unknown	Laan Lab, Human Genetics Research Group, University of Tartu Accession: SCV002538609.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022	Publications: PubMed (1) PubMed: 35535697 Number of individuals with the variant: 2 Clinical Features: Non-obstructive azoospermia (present) Secondary finding: yes Method: exome sequencing
Likely pathogenic (Jun 25, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 5 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002556766.2 First in ClinVar: Aug 08, 2022 Last updated: Dec 17, 2022
Pathogenic (Sep 23, 2022)	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: SCV000601562.4 First in ClinVar: Oct 09, 2016 Last updated: Jan 06, 2024	Publications: PubMed (31) PubMed: 30521064‚ 28514183‚ 34637943‚ 32658311‚ 31997046‚ 31589614‚ 30322717‚ 32635641‚ 33309985‚ 32719484‚ 29922827‚ 32832836‚ 32980694‚ 32427313‚ 31830689‚ 21056691‚ 18566915‚ 15483016‚ 16418736‚ 16525781‚ 21039432‚ 18409202‚ 22250089‚ 22949379‚ 21674763‚ 19072991‚ 27696107‚ 26832770‚ 28481244‚ 27398995‚ 27601186 Comment: The frequency of this variant in the general population, 0.00027 (5/18386 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the … (more) The frequency of this variant in the general population, 0.00027 (5/18386 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in multiple individuals with Lynch syndrome (PMID: 18566915 (2009), 26832770 (2016), 27601186 (2016), 18566915 (2009)), breast cancer (PMID: 32658311 (2021), 34637943 (2021)), prostate cancer (PMID: 32832836 (2020), or a Lynch syndrome associated cancer (PMID: 32635641 (2020), 30521064 (2019), 30322717 (2018), 27398995 (2016), 27696107 (2016), 19072991 (2009)). The variant has also been reported in the compound heterozygous state with other pathogenic MSH6 variants in individuals with a constitutional mismatch repair deficiency (CMMRD) syndrome phenotype (PMID: 21039432 (2011), 18409202 (2008), 16418736 (2006), 16525781 (2006)). Additionally, this variant has been shown to result in defective DNA repair when the variant is in the homozygous state or when coupled with another pathogenic MSH6 variant (PMID: 22250089 (2012)). Based on the available information, this variant is classified as pathogenic with reduced penetrance. This individual is at increased risk of developing MSH6 related cancers, though he/she is likely to have less cancer risk than individuals who are positive for other MSH6 pathogenic variants. (less)
Likely pathogenic (Aug 18, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003833660.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Likely pathogenic (Jul 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: SCV000690333.5 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024	Publications: PubMed (14) PubMed: 16418736‚ 16525781‚ 18409202‚ 18566915‚ 19072991‚ 21039432‚ 21056691‚ 21836479‚ 22250089‚ 22949379‚ 27696107‚ 28481244‚ 29785566‚ 30521064 Comment: This missense variant replaces arginine with cysteine at codon 1076 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on … (more) This missense variant replaces arginine with cysteine at codon 1076 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in heterozygous state in multiple individuals and families affected with Lynch syndrome-associated cancer (PMID: 18566915, 19072991, 21056691, 22949379, 27696107, 28481244, 30521064). This variant has been reported in at least five individuals found in trans with pathogenic MSH6 co-variants (compound heterozygous) who were affected with early-onset mismatch repair deficient colorectal cancer and/or polyps and some features of constitutional mismatch repair deficiency (CMMR-D) syndrome (PMID: 16418736, 16525781, 18409202, 21039432, 21836479, 22250089, 29785566). This variant was also detected in a homozygous individual affected with recurrent colorectal cancer in his 40s and multiple colorectal adenomas and polyps (PMID: 22250089). This variant has been identified in 24/251346 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
Pathogenic (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hereditary nonpolyposis colorectal neoplasms Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000283794.11 First in ClinVar: Mar 24, 2015 Last updated: Feb 14, 2024	Publications: PubMed (10) PubMed: 28492532‚ 21056691‚ 27696107‚ 18566915‚ 15483016‚ 16418736‚ 16525781‚ 21039432‚ 18409202‚ 22250089 Comment: This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1076 of the MSH6 protein … (more) This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1076 of the MSH6 protein (p.Arg1076Cys). This variant is present in population databases (rs63750617, gnomAD 0.03%). This missense change has been observed in individuals with clinical features of Lynch syndrome and also in unaffected individuals (PMID: 21056691, 27696107, 18566915, Invitae, external communication). Also, it has been observed in several individuals with constitutional mismatch repair deficiency (CMMR-D) syndrome. In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant (PMID: 15483016, 16418736, 16525781, 21039432, 18409202). These individuals were affected with early-onset colorectal cancer, glioblastoma, endometrial cancer, adenomatous polyposis, and/or cafe-au-lait spots. However, this variant was also found to be homozygous in individuals with mild CMMR-D features; these individuals were affected with colorectal cancer and kidney cancer (PMID: 22250089, Invitae). ClinVar contains an entry for this variant (Variation ID: 89357). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MSH6 protein function. For these reasons, this variant has been classified as Pathogenic. (less)
Likely Pathogenic (Jan 08, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004835010.1 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 (14) PubMed: 16418736‚ 16525781‚ 18409202‚ 18566915‚ 19072991‚ 21039432‚ 21056691‚ 21836479‚ 22250089‚ 22949379‚ 27696107‚ 28481244‚ 29785566‚ 30521064 Comment: This missense variant replaces arginine with cysteine at codon 1076 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on … (more) This missense variant replaces arginine with cysteine at codon 1076 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in heterozygous state in multiple individuals and families affected with Lynch syndrome-associated cancer (PMID: 18566915, 19072991, 21056691, 22949379, 27696107, 28481244, 30521064). This variant has been reported in at least five individuals found in trans with pathogenic MSH6 co-variants (compound heterozygous) who were affected with early-onset mismatch repair deficient colorectal cancer and/or polyps and some features of constitutional mismatch repair deficiency (CMMR-D) syndrome (PMID: 16418736, 16525781, 18409202, 21039432, 21836479, 22250089, 29785566). This variant was also detected in a homozygous individual affected with recurrent colorectal cancer in his 40s and multiple colorectal adenomas and polyps (PMID: 22250089). This variant has been identified in 24/251346 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less) Number of individuals with the variant: 3
Likely Pathogenic (Oct 14, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004847993.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Publications: PubMed (17) PubMed: 15483016‚ 18409202‚ 16418736‚ 16525781‚ 18566915‚ 19072991‚ 21039432‚ 28481244‚ 26832770‚ 22250089‚ 22949379‚ 27398995‚ 29785566‚ 27696107‚ 21056691‚ 27601186‚ 21836479 Comment: The p.Arg1076Cys variant in MSH6 has been reported in the heterozygous state in at least 12 individuals with Lynch syndrome-associated cancers (Plaschke 2004, Limburg 2011, … (more) The p.Arg1076Cys variant in MSH6 has been reported in the heterozygous state in at least 12 individuals with Lynch syndrome-associated cancers (Plaschke 2004, Limburg 2011, Liccardo 2017, Rohlin 2017, Rubio 2016, Schultheis 2016, Klarskov 2011, Schofield 2009, Nilbert 2009) and in the homozygous state in 1 individual with relatively late onset colorectal cancer, suggesting that it may be a hypomorphic allele (Gardes 2012). Additionally, the p.Arg1076Cys variant has also been reported in the compound heterozygous state in 5 individuals (from four families) with clinical features of constitutional mismatch repair deficiency (Okkels 2006, Plaschke 2006, Jasperson 2011, Gardes 2012). It has also been identified in 0.03% (5/18386) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Immunohistochemistry staining of tumor tissue samples in the majority of affected individuals showed loss of MSH6 staining, providing evidence that the Arg1076Cys variant may impact protein function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. This variant was classified as Likely Pathogenic on March 9, 2018 by the ClinGen-approved InSiGHT expert panel (RCV000074823.4). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PM3, PS4_Moderate, PS3_Supporting, PP3, PM2_Supporting. (less)
Likely 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: SCV002552331.6 First in ClinVar: Jul 23, 2022 Last updated: Aug 04, 2024
Likely pathogenic (Sep 01, 2023)	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: SCV001152299.27 First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024	Comment: MSH6: PM3:Strong, PM2, PS4:Moderate, PM5:Supporting Number of individuals with the variant: 3
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	Malignant tumor of breast 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: SCV001551385.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021	Comment: The MSH6 p.Arg1076Cys variant was identified in 10 of 5256 proband chromosomes (frequency: 0.002) from individuals or families with Lynch syndrome, early onset colorectal cancer, … (more) The MSH6 p.Arg1076Cys variant was identified in 10 of 5256 proband chromosomes (frequency: 0.002) from individuals or families with Lynch syndrome, early onset colorectal cancer, or endometrial cancer (Lagerstedt-Robinson 2016, Liccardo 2017, Limburg 2011, Nilbert 2009, Okkels 2012, Plaschke 2004, Rohlin 2017, Rubio 2016, Schofield 2009). The variant was also identified in dbSNP (ID: rs63750617) as â€šÃ„ÃºWith Pathogenic, Uncertain significance alleleâ€šÃ„Ã¹, ClinVar (classified as likely pathogenic by an InSiGHT expert panel in 2018, Ambry Genetics, GeneDx, and three other submitters; and as pathogenic by Invitae), and UMD-LSDB (3x classified neutral). The variant was identified in multiple cases with co-occurring, pathogenic MSH6 variants in patients with later-onset Lynch Syndrome-related cancers or mild Constitutional Mismatch Repair Deficiency-like phenotypes (Gardes 2012, Jasperson 2011, Okkels 2006, Okkels 2012, Plaschke 2006, Rahner 2007, Thompson 2013) as well as in the homozygous state in a patient with colorectal cancer at ages 45 and 49 (Gardes 2012), suggesting that this could be a hypomorphic variant. In vitro studies showed a normal transcript by RT-PCR RNA analysis, while Western blot analysis did not detect MSH6 protein (Thompson 2013, Gardes 2012).The variant was identified in control databases in 24 of 246118 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 15304 chromosomes (freq: 0.0001), Latino in 2 of 33554 chromosomes (freq: 0.00006), European in 9 of 111618 chromosomes (freq: 0.00008), Ashkenazi Jewish in 1 of 9846 chromosomes (freq: 0.0001), East Asian in 5 of 17240 chromosomes (freq: 0.0003), and South Asian in 5 of 30780 chromosomes (freq: 0.0002), while it was not observed in the Other or Finnish populations. The p.Arg1076 residue is conserved across mammals and other organisms and 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time, although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. (less)
Likely pathogenic (Aug 16, 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: SCV001786707.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021	Comment: Invasive Ductal Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Positive HER2 Receptor: Positive Age: 40-49 years
Likely pathogenic (Jun 21, 2019)	no assertion criteria provided Method: clinical testing	Lynch syndrome 5 Affected status: no Allele origin: unknown	University of Washington Department of Laboratory Medicine, University of Washington Accession: SCV002568086.1 First in ClinVar: Sep 03, 2022 Last updated: Sep 03, 2022	Publications: PubMed (1) PubMed: 18409202 Comment: This variant is present in the ClinVar database (ID: 89357) and is classified as likely pathogenic. It has been seen in individuals with constitutional mismatch … (more) This variant is present in the ClinVar database (ID: 89357) and is classified as likely pathogenic. It has been seen in individuals with constitutional mismatch repair deficiency (CMMRD) in conjunction with a second MSH6 mutation (Rahner 2008). In the heterozygous state, it has been seen in individuals with cancer however may be associated with a lower risk (hypomorphic) for cancer than other pathogenic MSH6 mutations (Rahner 2008). (less)
Pathogenic (Jul 01, 2021)	no assertion criteria provided Method: research	Gastric cancer Affected status: unknown Allele origin: germline	Laboratory for Genotyping Development, RIKEN Accession: SCV002758547.1 First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023	Publications: PubMed (1) PubMed: 36988593
Likely pathogenic (Jul 23, 2024)	no assertion criteria provided Method: clinical testing	MSH6-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005348075.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The MSH6 c.3226C>T variant is predicted to result in the amino acid substitution p.Arg1076Cys. This variant has been reported in individuals with colorectal, ovarian and … (more) The MSH6 c.3226C>T variant is predicted to result in the amino acid substitution p.Arg1076Cys. This variant has been reported in individuals with colorectal, ovarian and endometrial cancer with tumors exhibiting loss of MSH6 protein levels (Plaschke et al. 2004. PubMed ID: 15483016; Limburg et al. 2011. PubMed ID: 21056691; Thompson et al. 2013. PubMed ID: 22949379; Table S1, Carter et al. 2018. PubMed ID: 30322717; eTable 2, Jiang et al. 2019. PubMed ID: 30521064). It has been reported in the compound heterozygous state with other MSH6 pathogenic variants in individuals with early-onset colorectal cancer, and constitutional mismatch repair deficiency (Okkels et al. 2006. PubMed ID: 16525781; Rahner et al. 2008. PubMed ID: 18409202; Jasperson et al. 2011. PubMed ID: 21039432) and has been reported in the homozygous state in an individual with colorectal cancer (AlHarbi et al. 2023. PubMed ID: 37306523). This variant is reported in 0.027% of alleles in East Asian decent in gnomAD and is interpreted as likely pathogenic or pathogenic in ClinVar from multiple laboratories and the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/89357/). This variant is interpreted as likely pathogenic. (less)
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Comment:

The p.R1076C pathogenic mutation (also known as c.3226C>T), located in coding exon 5 of the MSH6 gene, results from a C to T substitution at nucleotide position 3226. The arginine at codon 1076 is replaced by cysteine, an amino acid with highly dissimilar properties. The in silico prediction for this alteration is inconclusive and this amino acid position is highly conserved in available vertebrate species. In one study, the p.R1076C mutation was detected in a male proband with colorectal cancer (CRC) at age 55 and a previous diagnosis of gastric cancer. The colorectal tumor of the proband demonstrated clonal loss of expression of both MSH2 and MSH6 proteins by immunohistochemistry (IHC). In addition, this individual's family history included a brother with CRC, an aunt with ovarian cancer, and a cousin with endometrial cancer (Schofield L et al. Int. J .Cancer. 2009 Sep;125:1492-3). The p.R1076C mutation was also reported in a 46-year-old man diagnosed with ascending colon cancer, but his tumor IHC testing showed intact staining for the MLH1, MSH2, and MSH6 proteins (Limburg PJ et al. Clin. Gastroenterol. Hepatol. 2011 Jun;9:497-502). Furthermore, the p.R1076C mutation was identified in a proband with a microsatellite stable endometrial cancer with intact staining for the MLH1, MSH2, and MSH6 proteins on IHC (Rubio I et al. Oncology. 2016 Jul;91(3):171-6). In addition, this mutation has been identified in multiple individuals whose Lynch syndrome-associated tumors displayed high microsatellite instability and/or had isolated loss of MSH6 on immunohistochemistry (IHC); however, at least two probands had intact staining on IHC (Ambry internal data). At least five individuals with features of CMMR-D have been reported to carry the p.R1076C mutation and a pathogenic (nonsense/frameshift) MSH6 mutation in trans, suggesting biallelic mismatch repair inactivation (Plaschke J et al. Eur. J. Hum. Genet. 2006 May;14:561-6; Okkels H et al. Int. J. Colorectal Dis. 2006 Dec;21:847-50; Rahner N et al. Am. J. Med. Genet. A. 2008 May;146A:1314-9; Jasperson KW et al. Clin. Genet. 2011 Oct;80:394-7). However, an individual found to be homozygous for this mutation did not present with classic CMMR-D symptoms and instead developed CRC at the ages of 45 and 49, suggesting that this variant may be hypomorphic. As risk estimates are unknown at this time, clinical correlation is advised. Based on the total supporting evidence, this alteration is interpreted as a disease-causing mutation, but may represent a low- or lower-penetrance MSH6 allele with regards to CMMR-D.

Comment:

Variant summary: MSH6 c.3226C>T (p.Arg1076Cys) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.5e-05 in 251346 control chromosomes (gnomAD). This frequency is lower than expected for a pathogenic variant in MSH6 causing Lynch Syndrome (9.5e-05 vs 0.00014), allowing no conclusion about variant significance. The variant, c.3226C>T, has been reported in compound heterozygous state with other pathogenic MSH6 truncating variants in several patients with constitutional mismatch repair deficiency (CMMRD) syndrome, i.e. early-onset colorectal cancer, adenomatous polyposis and cafe-au-lait spots (Okkels 2006, Plaschke 2006, Rahner 2008, Allred 2013). In many of these cases the loss of MSH6 staining in both the tumor and normal cells was described, pointing to a bi-allelic MSH6 mutation. The variant was also reported in heterozygosity in individuals affected by Lynch syndrome (Schofield 2009, Lagerstedt-Robinson 2016, Rohlin 2016, Liccardo 2017, Espenschied 2017, Kim_2022, Duzkale_2021), where in several cases the associated tumor demonstrated isolated loss of MSH6 staining. However, within the reported CMMRD families the variant was also observed in heterozygous state in unaffected family members (Plaschke 2006, Okkels 2006, Allred 2013), suggesting its role in causing Lynch syndrome is uncertain. This variant was also found in a homozygote who developed colorectal tumors at the age of 45 and 49 year, together with multiple colon adenomas and polyps (Gardes 2012), a disease history that is closer to Lynch syndrome than CMMRD. However, in LCLs derived from this patient, though MSH6 mRNA was detectable, Western blot analysis demonstrated the lack of MSH6 protein, a finding that is consistent with CMMRD (Gardes 2012). These data indicate that the variant may be a hypomorphic allele, though no functional studies are available to support this assumption. The following publications have been ascertained in the context of this evaluation (PMID: 34637943, 34271781, 28514183, 22250089, 35884469, 21836479, 27601186, 28481244, 21056691, 35725860, 36243179, 16525781, 16418736, 18409202, 27696107, 19072991, 23621914, 22949379, Allred_2013). ClinVar contains an entry for this variant (Variation ID: 89357). Based on the evidence outlined above, the variant was classified as likely pathogenic for constitutional mismatch repair deficiency (CMMRD) syndrome.

Comment:

Observed in individuals with a personal and/or family history of colorectal cancer, some with tumor studies demonstrating loss of MSH6 protein expression (PMID: 18566915, 19072991, 21056691, 27398995, 26832770, 28481244, 27696107, 33194656); May be a hypomorphic allele as it was observed in the homozygous state in patients with relatively late onset colorectal cancer/CMMR-D, and, among heterozygotes, a limited number of Lynch-associated cancers have been observed in multiple internal and published families (PMID: 16525781, 18409202, 22250089, 38789506); 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: 22949379, 15483016, 20531397, 22886683, 32980694, 31830689, 34637943, 29922827, 28888541, 32832836, 32029870, 33194656, 17531815, 21120944, 23621914, 18566915, 21674763, 21056691, 16525781, 16418736, 18409202, 19072991, 21039432, 26832770, 24012250, 27398995, 22250089, 18709565, 27601186, 27696107, 29785566, 28481244, 21836479, 22495361, 21376568, 30521064, 30322717, 32635641, 31721094, 31997046, 31447099, 32658311, 33422121, 31589614, 33309985, 37306523, 35861108, 36744932, 31391288, 36243179, 37175550, 34308104, 34873480, 35725860, 32719484, 30787465, 33087929, 32427313, 34445333, 33365374, 35535697, 37728764, 30608896, 38789506)

Comment:

This c.3226C>T (p.Arg1076Cys) variant in the MSH6 gene has been reported in the homozygous state in 1 individual with colorectal cancer (PMID: 22250089). It has also been reported in trans configuration with a pathogenic variant in 3 unrelated individuals with autosomal recessive hereditary nonpolyposis colorectal cancer type 5 (HNPCC5; PMID: 16418736, 16525781, 18409202) and in 2 related individuals with mismatch repair cancer syndrome (MMRCS; MIM 600678; PMID: 21039432). Segregation studies in this family confirmed that the c.3226C>T (p.Arg1076Cys) variant segregated together with a second pathogenic variant in the 2 affected individuals, but not in 6 unaffected family members (PMID: 21039432). The c.3226C>T variant is very rare in the general population. While not validated for clinical use, the computer-based algorithms PolyPhen-2 and SIFT predict the p.Arg1076Cys change to be deleterious. Based on this information, the c.3226C>T (p.Arg1076Cys) variant in the MSH6 gene is classified as likely pathogenic.

Comment:

The MSH6 c.3226C>T; p.Arg1076Cys variant (rs63750617) is reported in the literature in multiple heterozygous individuals affected with Lynch syndrome (Lagerstedt-Robinson 2016, Liccardo 2017, Schofield 2009). This variant has also been reported in trans to another pathogenic variant in multiple individuals with symptoms consistent with constitutional mismatch repair deficiency (CMMRD) syndrome (Gardes 2012, Jasperson 2011, Okkels 2006, Plaschke 2006). However, the p.Arg1076Cys variant has also been found in a homozygous individual with symptoms more consistent with Lynch syndrome (Gardes 2012), as well as in healthy heterozygous relatives of affected individuals (Jasperson 2011, Okkels 2006, Plaschke 2006), suggesting it may exhibit incomplete penetrance. This variant is found in the general population with a low overall allele frequency of 0.01% (24/251346 alleles) in the Genome Aggregation Database. The arginine at codon 1076 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.849). Patient cells carrying this variant exhibit reduced resolution of irradiation-induced DNA damage foci compared to control cells (Gardes 2012), suggesting reduced DNA damage repair activity. Based on available information, this variant is considered to be likely pathogenic. References: Gardes P et al. Human MSH6 deficiency is associated with impaired antibody maturation. J Immunol. 2012 Feb 15;188(4):2023-9. Jasperson KW et al. Constitutional mismatch repair-deficiency syndrome presenting as colonic adenomatous polyposis: clues from the skin. Clin Genet. 2011 Oct;80(4):394-7. Lagerstedt-Robinson K et al. Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population. Oncol Rep. 2016 Nov;36(5):2823-2835. Liccardo R, De Rosa M, Rossi GB, Carlomagno N, Izzo P, Duraturo F. Incomplete Segregation of MSH6 Frameshift Variants with Phenotype of Lynch Syndrome. Int J Mol Sci. 2017 May 6;18(5):999. Okkels H et al. Polyposis and early cancer in a patient with low penetrant mutations in MSH6 and APC: hereditary colorectal cancer as a polygenic trait. Int J Colorectal Dis. 2006 Dec;21(8):847-50. Plaschke J et al. Compound heterozygosity for two MSH6 mutations in a patient with early onset of HNPCC-associated cancers, but without hematological malignancy and brain tumor. Eur J Hum Genet. 2006 May;14(5):561-6. Schofield L et al. Population-based detection of Lynch syndrome in young colorectal cancer patients using microsatellite instability as the initial test. Int J Cancer. 2009 Mar 1;124(5):1097-102.

Comment:

The frequency of this variant in the general population, 0.00027 (5/18386 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in multiple individuals with Lynch syndrome (PMID: 18566915 (2009), 26832770 (2016), 27601186 (2016), 18566915 (2009)), breast cancer (PMID: 32658311 (2021), 34637943 (2021)), prostate cancer (PMID: 32832836 (2020), or a Lynch syndrome associated cancer (PMID: 32635641 (2020), 30521064 (2019), 30322717 (2018), 27398995 (2016), 27696107 (2016), 19072991 (2009)). The variant has also been reported in the compound heterozygous state with other pathogenic MSH6 variants in individuals with a constitutional mismatch repair deficiency (CMMRD) syndrome phenotype (PMID: 21039432 (2011), 18409202 (2008), 16418736 (2006), 16525781 (2006)). Additionally, this variant has been shown to result in defective DNA repair when the variant is in the homozygous state or when coupled with another pathogenic MSH6 variant (PMID: 22250089 (2012)). Based on the available information, this variant is classified as pathogenic with reduced penetrance. This individual is at increased risk of developing MSH6 related cancers, though he/she is likely to have less cancer risk than individuals who are positive for other MSH6 pathogenic variants.

Comment:

This missense variant replaces arginine with cysteine at codon 1076 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in heterozygous state in multiple individuals and families affected with Lynch syndrome-associated cancer (PMID: 18566915, 19072991, 21056691, 22949379, 27696107, 28481244, 30521064). This variant has been reported in at least five individuals found in trans with pathogenic MSH6 co-variants (compound heterozygous) who were affected with early-onset mismatch repair deficient colorectal cancer and/or polyps and some features of constitutional mismatch repair deficiency (CMMR-D) syndrome (PMID: 16418736, 16525781, 18409202, 21039432, 21836479, 22250089, 29785566). This variant was also detected in a homozygous individual affected with recurrent colorectal cancer in his 40s and multiple colorectal adenomas and polyps (PMID: 22250089). This variant has been identified in 24/251346 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

Comment:

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1076 of the MSH6 protein (p.Arg1076Cys). This variant is present in population databases (rs63750617, gnomAD 0.03%). This missense change has been observed in individuals with clinical features of Lynch syndrome and also in unaffected individuals (PMID: 21056691, 27696107, 18566915, Invitae, external communication). Also, it has been observed in several individuals with constitutional mismatch repair deficiency (CMMR-D) syndrome. In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant (PMID: 15483016, 16418736, 16525781, 21039432, 18409202). These individuals were affected with early-onset colorectal cancer, glioblastoma, endometrial cancer, adenomatous polyposis, and/or cafe-au-lait spots. However, this variant was also found to be homozygous in individuals with mild CMMR-D features; these individuals were affected with colorectal cancer and kidney cancer (PMID: 22250089, Invitae). ClinVar contains an entry for this variant (Variation ID: 89357). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MSH6 protein function. For these reasons, this variant has been classified as Pathogenic.

Comment:

The p.Arg1076Cys variant in MSH6 has been reported in the heterozygous state in at least 12 individuals with Lynch syndrome-associated cancers (Plaschke 2004, Limburg 2011, Liccardo 2017, Rohlin 2017, Rubio 2016, Schultheis 2016, Klarskov 2011, Schofield 2009, Nilbert 2009) and in the homozygous state in 1 individual with relatively late onset colorectal cancer, suggesting that it may be a hypomorphic allele (Gardes 2012). Additionally, the p.Arg1076Cys variant has also been reported in the compound heterozygous state in 5 individuals (from four families) with clinical features of constitutional mismatch repair deficiency (Okkels 2006, Plaschke 2006, Jasperson 2011, Gardes 2012). It has also been identified in 0.03% (5/18386) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Immunohistochemistry staining of tumor tissue samples in the majority of affected individuals showed loss of MSH6 staining, providing evidence that the Arg1076Cys variant may impact protein function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. This variant was classified as Likely Pathogenic on March 9, 2018 by the ClinGen-approved InSiGHT expert panel (RCV000074823.4). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PM3, PS4_Moderate, PS3_Supporting, PP3, PM2_Supporting.

Comment:

The MSH6 p.Arg1076Cys variant was identified in 10 of 5256 proband chromosomes (frequency: 0.002) from individuals or families with Lynch syndrome, early onset colorectal cancer, or endometrial cancer (Lagerstedt-Robinson 2016, Liccardo 2017, Limburg 2011, Nilbert 2009, Okkels 2012, Plaschke 2004, Rohlin 2017, Rubio 2016, Schofield 2009). The variant was also identified in dbSNP (ID: rs63750617) as â€šÃ„ÃºWith Pathogenic, Uncertain significance alleleâ€šÃ„Ã¹, ClinVar (classified as likely pathogenic by an InSiGHT expert panel in 2018, Ambry Genetics, GeneDx, and three other submitters; and as pathogenic by Invitae), and UMD-LSDB (3x classified neutral). The variant was identified in multiple cases with co-occurring, pathogenic MSH6 variants in patients with later-onset Lynch Syndrome-related cancers or mild Constitutional Mismatch Repair Deficiency-like phenotypes (Gardes 2012, Jasperson 2011, Okkels 2006, Okkels 2012, Plaschke 2006, Rahner 2007, Thompson 2013) as well as in the homozygous state in a patient with colorectal cancer at ages 45 and 49 (Gardes 2012), suggesting that this could be a hypomorphic variant. In vitro studies showed a normal transcript by RT-PCR RNA analysis, while Western blot analysis did not detect MSH6 protein (Thompson 2013, Gardes 2012).The variant was identified in control databases in 24 of 246118 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 15304 chromosomes (freq: 0.0001), Latino in 2 of 33554 chromosomes (freq: 0.00006), European in 9 of 111618 chromosomes (freq: 0.00008), Ashkenazi Jewish in 1 of 9846 chromosomes (freq: 0.0001), East Asian in 5 of 17240 chromosomes (freq: 0.0003), and South Asian in 5 of 30780 chromosomes (freq: 0.0002), while it was not observed in the Other or Finnish populations. The p.Arg1076 residue is conserved across mammals and other organisms and 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time, although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.

Comment:

This variant is present in the ClinVar database (ID: 89357) and is classified as likely pathogenic. It has been seen in individuals with constitutional mismatch repair deficiency (CMMRD) in conjunction with a second MSH6 mutation (Rahner 2008). In the heterozygous state, it has been seen in individuals with cancer however may be associated with a lower risk (hypomorphic) for cancer than other pathogenic MSH6 mutations (Rahner 2008).

Comment:

The MSH6 c.3226C>T variant is predicted to result in the amino acid substitution p.Arg1076Cys. This variant has been reported in individuals with colorectal, ovarian and endometrial cancer with tumors exhibiting loss of MSH6 protein levels (Plaschke et al. 2004. PubMed ID: 15483016; Limburg et al. 2011. PubMed ID: 21056691; Thompson et al. 2013. PubMed ID: 22949379; Table S1, Carter et al. 2018. PubMed ID: 30322717; eTable 2, Jiang et al. 2019. PubMed ID: 30521064). It has been reported in the compound heterozygous state with other MSH6 pathogenic variants in individuals with early-onset colorectal cancer, and constitutional mismatch repair deficiency (Okkels et al. 2006. PubMed ID: 16525781; Rahner et al. 2008. PubMed ID: 18409202; Jasperson et al. 2011. PubMed ID: 21039432) and has been reported in the homozygous state in an individual with colorectal cancer (AlHarbi et al. 2023. PubMed ID: 37306523). This variant is reported in 0.027% of alleles in East Asian decent in gnomAD and is interpreted as likely pathogenic or pathogenic in ClinVar from multiple laboratories and the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/89357/). This variant is interpreted as likely pathogenic.

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
Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer.	Usui Y	The New England journal of medicine	2023	PMID: 36988593
Hereditary cancer variants and homologous recombination deficiency in biliary tract cancer.	Okawa Y	Journal of hepatology	2023	PMID: 36243179
Identification of Lynch Syndrome in Patients with Endometrial Cancer Based on a Germline Next Generation Sequencing Multigene Panel Test.	Kim YN	Cancers	2022	PMID: 35884469
Presence of rare potential pathogenic variants in subjects under 65 years old with very severe or fatal COVID-19.	López-Rodríguez R	Scientific reports	2022	PMID: 35725860
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
Population-based Screening for Hereditary Colorectal Cancer Variants in Japan.	Fujita M	Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association	2022	PMID: 33309985
Concurrent pathogenic variations in patients with hereditary cancer syndromes.	Agaoglu NB	European journal of medical genetics	2021	PMID: 34637943
Investigation of Hereditary Cancer Predisposition Genes of Patients with Colorectal Cancer: Single-centre Experience.	Duzkale N	Journal of the College of Physicians and Surgeons--Pakistan : JCPSP	2021	PMID: 34271781
Germline pathogenic variant spectrum in 25 cancer susceptibility genes in Turkish breast and colorectal cancer patients and elderly controls.	Akcay IM	International journal of cancer	2021	PMID: 32658311
Genetic characterization of pancreatic cancer patients and prediction of carrier status of germline pathogenic variants in cancer-predisposing genes.	Mizukami K	EBioMedicine	2020	PMID: 32980694
Pathogenic Variants in Cancer Predisposition Genes and Prostate Cancer Risk in Men of African Ancestry.	Matejcic M	JCO precision oncology	2020	PMID: 32832836
Population genetic screening efficiently identifies carriers of autosomal dominant diseases.	Grzymski JJ	Nature medicine	2020	PMID: 32719484
Comprehensive Constitutional Genetic and Epigenetic Characterization of Lynch-Like Individuals.	Dámaso E	Cancers	2020	PMID: 32635641
Contribution of Germline Predisposition Gene Mutations to Breast Cancer Risk in African American Women.	Palmer JR	Journal of the National Cancer Institute	2020	PMID: 32427313
Detection of DNA mismatch repair deficient crypts in random colonoscopic biopsies identifies Lynch syndrome patients.	Brand RE	Familial cancer	2020	PMID: 31997046
Variants of DNA mismatch repair genes derived from 33,998 Chinese individuals with and without cancer reveal their highly ethnic-specific nature.	Zhang L	European journal of cancer (Oxford, England : 1990)	2020	PMID: 31830689
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes.	Capalbo A	PLoS genetics	2019	PMID: 31589614
Universal screening for Lynch syndrome in a large consecutive cohort of Chinese colorectal cancer patients: High prevalence and unique molecular features.	Jiang W	International journal of cancer	2019	PMID: 30521064
Delineating a new feature of constitutional mismatch repair deficiency (CMMRD) syndrome: breast cancer.	Bush L	Familial cancer	2019	PMID: 29785566
Germline pathogenic variants identified in women with ovarian tumors.	Carter NJ	Gynecologic oncology	2018	PMID: 30322717
Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer.	Hu C	JAMA	2018	PMID: 29922827
Multigene Panel Testing Provides a New Perspective on Lynch Syndrome.	Espenschied CR	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2017	PMID: 28514183
Incomplete Segregation of MSH6 Frameshift Variants with Phenotype of Lynch Syndrome.	Liccardo R	International journal of molecular sciences	2017	PMID: 28481244
Expanding the genotype-phenotype spectrum in hereditary colorectal cancer by gene panel testing.	Rohlin A	Familial cancer	2017	PMID: 27696107
Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population.	Lagerstedt-Robinson K	Oncology reports	2016	PMID: 27601186
Analysis of Lynch Syndrome Mismatch Repair Genes in Women with Endometrial Cancer.	Rubio I	Oncology	2016	PMID: 27398995
Massively Parallel Sequencing-Based Clonality Analysis of Synchronous Endometrioid Endometrial and Ovarian Carcinomas.	Schultheis AM	Journal of the National Cancer Institute	2016	PMID: 26832770
CoDP: predicting the impact of unclassified genetic variants in MSH6 by the combination of different properties of the protein.	Terui H	Journal of biomedical science	2013	PMID: 23621914
A multifactorial likelihood model for MMR gene variant classification incorporating probabilities based on sequence bioinformatics and tumor characteristics: a report from the Colon Cancer Family Registry.	Thompson BA	Human mutation	2013	PMID: 22949379
MSH6 mutations are frequent in hereditary nonpolyposis colorectal cancer families with normal pMSH6 expression as detected by immunohistochemistry.	Okkels H	Applied immunohistochemistry & molecular morphology : AIMM	2012	PMID: 22495361
Human MSH6 deficiency is associated with impaired antibody maturation.	Gardès P	Journal of immunology (Baltimore, Md. : 1950)	2012	PMID: 22250089
Challenges in the identification of MSH6-associated colorectal cancer: rectal location, less typical histology, and a subset with retained mismatch repair function.	Klarskov L	The American journal of surgical pathology	2011	PMID: 21836479
High-grade brain tumors in siblings with biallelic MSH6 mutations.	Ilencikova D	Pediatric blood & cancer	2011	PMID: 21674763
Prevalence of alterations in DNA mismatch repair genes in patients with young-onset colorectal cancer.	Limburg PJ	Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association	2011	PMID: 21056691
Constitutional mismatch repair-deficiency syndrome presenting as colonic adenomatous polyposis: clues from the skin.	Jasperson KW	Clinical genetics	2011	PMID: 21039432
Population-based detection of Lynch syndrome in young colorectal cancer patients using microsatellite instability as the initial test.	Schofield L	International journal of cancer	2009	PMID: 19072991
Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population.	Nilbert M	Familial cancer	2009	PMID: 18566915
Compound heterozygosity for two MSH6 mutations in a patient with early onset colorectal cancer, vitiligo and systemic lupus erythematosus.	Rahner N	American journal of medical genetics. Part A	2008	PMID: 18409202
Polyposis and early cancer in a patient with low penetrant mutations in MSH6 and APC: hereditary colorectal cancer as a polygenic trait.	Okkels H	International journal of colorectal disease	2006	PMID: 16525781
Compound heterozygosity for two MSH6 mutations in a patient with early onset of HNPCC-associated cancers, but without hematological malignancy and brain tumor.	Plaschke J	European journal of human genetics : EJHG	2006	PMID: 16418736
Lower incidence of colorectal cancer and later age of disease onset in 27 families with pathogenic MSH6 germline mutations compared with families with MLH1 or MSH2 mutations: the German Hereditary Nonpolyposis Colorectal Cancer Consortium.	Plaschke J	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2004	PMID: 15483016
http://www.insight-database.org/classifications/?gene=MSH6&variant=c.3226C%3ET	-	-	-	-
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Text-mined citations for rs63750617 ...

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_000179.3(MSH6):c.3226C>T (p.Arg1076Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs63750617 ...