VCV000089363.87 - ClinVar

NM_000179.3(MSH6):c.3261del (p.Phe1088fs)

Germline

Top reviewed classifications are shown here.

Submission summary:

32 submissions

31 submitters

11 conditions

Reviewed by expert panel

Pathogenic

Sep 2013 by International …

for Lynch Syndrome

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000179.3(MSH6):c.3261del (p.Phe1088fs)

Variation ID: 89363 Accession: VCV000089363.87

Type and length

Deletion, 1 bp

Location

Cytogenetic: 2p16.3 2: 47803501 (GRCh38) [ NCBI UCSC ] 2: 48030640 (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	Mar 24, 2015	Jan 13, 2025	Sep 5, 2013

HGVS

Nucleotide	Protein	Molecular consequence
NM_000179.3:c.3261del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000170.1:p.Phe1088fs	frameshift
NM_000179.3:c.3261delC MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000179.2:c.3261delC
NM_001281492.2:c.2871del	NP_001268421.1:p.Phe958fs	frameshift
NM_001281493.1:c.2355delC
NM_001281493.2:c.2355del	NP_001268422.1:p.Phe786fs	frameshift
NM_001281494.2:c.2355del	NP_001268423.1:p.Phe786fs	frameshift
NC_000002.12:g.47803508del
NC_000002.11:g.48030647del
NG_007111.1:g.25362del
LRG_219:g.25362del

... more HGVS ... less HGVS

Protein change

F958fs, F786fs

Other names

Canonical SPDI

NC_000002.12:47803500:CCCCCCCC:CCCCCCC

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.

Links

ClinGen: CA012327 OMIM: 600678.0017 dbSNP: rs267608078 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	9287	9607

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.
Mismatch repair cancer syndrome 3	Pathogenic (1)	no assertion criteria provided	Nov 1, 2007	RCV000009499.7
Lynch syndrome	Pathogenic (5)	reviewed by expert panel	Sep 5, 2013	RCV000074830.16
Hereditary cancer-predisposing syndrome	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Sep 20, 2024	RCV000115411.18
not provided	Pathogenic (10)	criteria provided, multiple submitters, no conflicts	Jul 31, 2024	RCV000202045.51
Hereditary nonpolyposis colorectal neoplasms	Pathogenic (1)	criteria provided, single submitter	Jan 24, 2024	RCV000524165.11
Lynch-like syndrome	Pathogenic (1)	no assertion criteria provided	Jul 1, 2019	RCV001249957.2
Carcinoma of colon	Pathogenic (1)	no assertion criteria provided	-	RCV001353984.3
Endometrial carcinoma	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Feb 23, 2024	RCV001762178.7
Lynch syndrome 5	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Jun 28, 2024	RCV001824596.7
Endometrial carcinoma Lynch syndrome 5 Mismatch repair cancer syndrome 3	Pathogenic (1)	criteria provided, single submitter	Dec 14, 2021	RCV002498358.2
Gastric cancer	Pathogenic (1)	no assertion criteria provided	Jul 1, 2021	RCV003162476.2
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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.
Pathogenic (Sep 05, 2013)	reviewed by expert panel (Guidelines v1.9) Method: research	Lynch Syndrome Affected status: unknown Allele origin: germline	International Society for Gastrointestinal Hereditary Tumours (InSiGHT) Accession: SCV000108041.3 First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022 Comment: Classified with v1.9 guidelines: https://docs.google.com/file/d/0B3JL6rP6JzhoN2EydHRVMEI1UGs	Comment: Coding sequence variation resulting in a stop codon
Pathogenic (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Endometrial carcinoma Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002517643.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
Pathogenic (Dec 14, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Endometrial carcinoma Lynch syndrome 5 Mismatch repair cancer syndrome 3 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002810377.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 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: SCV002010094.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023
Pathogenic (Jan 05, 2021)	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: SCV000601570.5 First in ClinVar: Sep 28, 2017 Last updated: Jan 06, 2024	Publications: PubMed (25) PubMed: 29371908‚ 32042422‚ 32008151‚ 10508506‚ 26681312‚ 30093976‚ 30322717‚ 30730459‚ 30787465‚ 31447099‚ 26787237‚ 26318770‚ 20587412‚ 20487569‚ 20007843‚ 19526325‚ 17117178‚ 31845022‚ 31921681‚ 32719484‚ 32832836‚ 33087929‚ 22734033‚ 20028993‚ 20591884 Comment: This variant alters the translational reading frame of the MSH6 mRNA and causes the premature termination of MSH6 protein synthesis. In the published literature, this … (more) This variant alters the translational reading frame of the MSH6 mRNA and causes the premature termination of MSH6 protein synthesis. In the published literature, this variant has been reported in individuals affected with a Lynch syndrome associated cancer (PMIDs: 20028993 (2010), 20591884 (2010), 22734033 (2012), 26787237 (2016), 29371908 (2018)) and CMMRD (PMID: 32042422 (2020)). The frequency of this variant in the general population, 0.000014 (4/280876 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. (less)
Pathogenic (Jan 04, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002017593.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Feb 17, 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: SCV000685379.4 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024	Publications: PubMed (10) PubMed: 15236168‚ 15483016‚ 17117178‚ 17557300‚ 20007843‚ 20487569‚ 20587412‚ 22480969‚ 22734033‚ 27064304 Comment: This variant deletes 1 nucleotide in exon 5 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more) This variant deletes 1 nucleotide in exon 5 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals and families affected with Lynch syndrome, Muir-Torre syndrome, or constitutional mismatch repair deficiency syndrome (PMID: 15236168, 15483016, 17117178, 17557300, 20007843, 20487569, 20587412, 22480969, 22734033, 27064304). This variant has been identified in 1/30714 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
Pathogenic (Jan 24, 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: SCV000255262.13 First in ClinVar: Oct 11, 2015 Last updated: Feb 14, 2024	Publications: PubMed (11) PubMed: 28492532‚ 18269114‚ 24362816‚ 10508506‚ 15483016‚ 18301448‚ 20007843‚ 20028993‚ 20587412‚ 20591884‚ 22734033 Comment: This sequence change creates a premature translational stop signal (p.Phe1088Serfs2) in the MSH6 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Phe1088Serfs2) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 10508506, 15483016, 18301448, 20007843, 20028993, 20587412, 20591884, 22734033). ClinVar contains an entry for this variant (Variation ID: 89363). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Feb 23, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Endometrial carcinoma Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004195755.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Jun 28, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 5 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Department of Human Genetics, Hannover Medical School Accession: SCV005062157.1 First in ClinVar: Jun 29, 2024 Last updated: Jun 29, 2024	Clinical Features: Breast carcinoma (present)
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: SCV005090499.1 First in ClinVar: Aug 04, 2024 Last updated: Aug 04, 2024
Pathogenic (Aug 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: SCV001250452.27 First in ClinVar: May 12, 2020 Last updated: Dec 22, 2024	Comment: MSH6: PVS1, PS4:Moderate Number of individuals with the variant: 5
Pathogenic (Sep 20, 2024)	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: SCV000187451.10 First in ClinVar: Aug 06, 2014 Last updated: Jan 13, 2025	Publications: PubMed (10) PubMed: 17117178‚ 18269114‚ 22480969‚ 27064304‚ 30093976‚ 30322717‚ 31845022‚ 32042422‚ 32832836‚ 34425783 Comment: The c.3261delC pathogenic mutation, located in coding exon 5 of the MSH6 gene, results from a deletion of one nucleotide at nucleotide position 3261, causing … (more) The c.3261delC pathogenic mutation, located in coding exon 5 of the MSH6 gene, results from a deletion of one nucleotide at nucleotide position 3261, causing a translational frameshift with a predicted alternate stop codon (p.F1088Sfs*2). This mutation has been reported in multiple hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome families; several whose LS-associated tumors demonstrating high microsatellite instability and/or loss of MSH6 staining by immunohistochemistry (IHC) (Wijnen J et al. Nat. Genet. 1999 Oct;23:142-4; Kets CM et al. Br J Cancer, 2006 Dec;95:1678-82; Devlin LA et al. Ulster Med J, 2008 Jan;77:25-30; Talseth-Palmer BA et al. Hered. Cancer Clin. Pract. 2010 May;8:5; van der Post RS et al. J. Med. Genet. 2010 Jul;47:464-70; Bonnet D et al. Dig Liver Dis, 2012 Jun;44:515-22; Sjursen W et al. Mol Genet Genomic Med, 2016 Mar;4:223-31; Lagerstedt-Robinson K et al. Oncol Rep. 2016 Nov;36(5):2823-2835; Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43; Ylmaz A et al. Int J Colorectal Dis, 2020 Feb;35:351-353). This mutation has also been reported in the homozygous state as well as compound heterozygous with a second mutation in MSH6 in several patients with Constitutional Mismatch Repair Deficiency (CMMRD) syndrome (Auclair J et al. Hum Mutat. 2007 Nov;28(11):1084-90; Xu M et al. Biomed Rep, 2020 Mar;12:134-138; Ando T et al. BMC Gastroenterol, 2021 Aug;21:326). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (Aug 29, 2016)	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: SCV000695853.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017	Publications: PubMed (9) PubMed: 19526325‚ 22480969‚ 17557300‚ 20487569‚ 17117178‚ 27064304‚ 21674763‚ 20007843‚ 20591884 Comment: Variant summary: The MSH6 c.3261delC (p.Phe1088Serfs) variant results in a premature termination codon, predicted to cause a truncated or absent MSH6 protein due to nonsense … (more) Variant summary: The MSH6 c.3261delC (p.Phe1088Serfs) variant results in a premature termination codon, predicted to cause a truncated or absent MSH6 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Arg1172fs). One in silico tool predicts a damaging outcome for this variant. This variant was found in 21/120336 control chromosomes at a frequency of 0.0001745, which is approximately equal to the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). However, the variant has been reported in many HNPCC patients in the literature in heterozygous state. The variant has also been cited in homozygous and compound heterozygous states in patients with early onset cancer phenotypes (Ilencikova_PedBlodCanc_2011 and Auclair_HumMut_2007, respectively). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
Pathogenic (Dec 18, 2017)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	Not Provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000884140.1 First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017	Comment: The MSH6 c.3261delC, p.Phe1088fs variant (rs267608078) is a recurrent alteration in individuals diagnosed with hereditary nonpolyposis colorectal cancer and other familial cancers (Baglietto 2010, Lavoine … (more) The MSH6 c.3261delC, p.Phe1088fs variant (rs267608078) is a recurrent alteration in individuals diagnosed with hereditary nonpolyposis colorectal cancer and other familial cancers (Baglietto 2010, Lavoine 2015, Tavakkol 2012, van der Post 2010, Wijnen 1999). It is classified as pathogenic in ClinVar (Variation ID: 89363), and observed once in the Genome Aggregation Database general population database (1/30714 alleles). The variant introduces a frameshift, and is predicted to result in a truncated protein or an absent transcript. Based on the above information, the variant is classified as pathogenic. References: Baglietto L et al. Risks of Lynch syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst. 2010; 102(3):193-201. Lavoine N et al. Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort. J Med Genet. 2015; 52(11):770-8. Tavakkol Z et al. Germline mutation in MSH6 associated with multiple malignant neoplasms in a patient With Muir-Torre syndrome. J Clin Oncol. 2012; 30(22):e195-8. van der Post R et al. Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers. J Med Genet. 2010; 47(7):464-70. Wijnen J et al. Familial endometrial cancer in female carriers of MSH6 germline mutations. Nat Genet. 1999; 23(2):142-4. (less)
Pathogenic (Sep 01, 2014)	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: SCV001449559.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Number of individuals with the variant: 3
Pathogenic (May 30, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 5 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002580158.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PVS1, PS4_MOD, PM2_SUP, PM3_SUP	Number of individuals with the variant: 1 Sex: female
Pathogenic (Jul 24, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002761956.1 First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022
Pathogenic (Dec 06, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Endometrial carcinoma Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV002765104.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Comment: _x000D_ Criteria applied: PVS1, PS4_MOD
Pathogenic (Nov 18, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000149320.17 First in ClinVar: May 17, 2014 Last updated: Mar 04, 2023	Comment: Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more) Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek 2016); Observed in the heterozygous state in patients with Lynch-related cancers consistent with pathogenic variants in this gene (Plaschke 2004, Hampel 2005, Baglietto 2010, Sjursen 2010, Talseth-Palmer 2010, Meric-Bernstam 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 26552419, 26787237, 15872200, 29371908, 20591884, 20028993, 15483016, 20487569, 20587412, 26866578, 27601186, 27486176, 25980754, 10508506, 22734033, 26681312, 28528517, 26318770, 30730459, 30322717, 30093976, 31447099, 31845022, 31921681, 32832836, 32042422, 17557300, 32719484, 30787465, 33087929) (less)
Pathogenic (Sep 14, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome 5 (Autosomal dominant inheritance) Affected status: yes Allele origin: maternal	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV004100797.1 First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023	Comment: Criteria applied: PVS1,PS4,PM2_SUP Clinical Features: Family history of cancer (present) Sex: male
Pathogenic (Aug 22, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Lynch syndrome 5 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004187417.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Comment: This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Pathogenic (Feb 06, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lynch syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000711434.3 First in ClinVar: Apr 09, 2018 Last updated: Apr 20, 2024	Publications: PubMed (3) PubMed: 26318770‚ 20028993‚ 26787237 Comment: The p.Phe1088SerfsX2 variant in MSH6 has been reported in the heterozygous state in >5 individuals with MSH6-associated cancers (Baglietto 2010 PMID: 20028993, Meric-Bernstam 2016 PMID: … (more) The p.Phe1088SerfsX2 variant in MSH6 has been reported in the heterozygous state in >5 individuals with MSH6-associated cancers (Baglietto 2010 PMID: 20028993, Meric-Bernstam 2016 PMID: 26787237), and in the compound heterozygous state in 1 individual with constitutional mismatch repair deficiency syndrome (CMMRD) who also carried another MSH6 variant (Lavoine 2015 PMID: 26318770). This variant has been identified in 0.01% (1/10370) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). It is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1088 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of function of the MSH6 gene is an established disease mechanism in Lynch Syndrome. Furthermore, this variant was classified as Pathogenic on Sept. 5, 2013 by the ClinGen-approved InSiGHT Expert Panel (ClinVar Variation ID: 89363). In summary, this variant meets criteria to be classified as pathogenic for Lynch Syndrome in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4_Supporting, PM2_Supporting, PVS1. (less)
Pathogenic (Feb 02, 2024)	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: SCV005199212.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Sep 09, 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: SCV004835021.2 First in ClinVar: Apr 20, 2024 Last updated: Dec 14, 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 (10) PubMed: 15236168‚ 15483016‚ 17117178‚ 17557300‚ 20007843‚ 20487569‚ 20587412‚ 22480969‚ 22734033‚ 27064304 Comment: This variant deletes 1 nucleotide in exon 5 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more) This variant deletes 1 nucleotide in exon 5 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome, Muir-Torre syndrome and constitutional mismatch repair deficiency syndrome (PMID: 15236168, 15483016, 17117178, 17557300, 20007843, 20487569, 20587412, 22480969, 22734033, 27064304). This variant has been identified in 1/30714 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less) Number of individuals with the variant: 7 Zygosity: Single Heterozygote
Pathogenic (Jul 01, 2019)	no assertion criteria provided Method: clinical testing	Lynch-like syndrome Affected status: yes Allele origin: somatic	Constitutional Genetics Lab, Leon Berard Cancer Center Accession: SCV001423971.1 First in ClinVar: Jul 27, 2020 Last updated: Jul 27, 2020	Number of individuals with the variant: 8
Pathogenic (Nov 01, 2007)	no assertion criteria provided Method: literature only	MISMATCH REPAIR CANCER SYNDROME 3 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000029717.4 First in ClinVar: Apr 04, 2013 Last updated: Nov 28, 2020	Publications: PubMed (1) PubMed: 17557300 Comment on evidence: For discussion of the 1-bp deletion in the MSH6 gene (c.3261delC, NM_000179.1) that was found in compound heterozygous state in a patient with mismatch repair … (more) For discussion of the 1-bp deletion in the MSH6 gene (c.3261delC, NM_000179.1) that was found in compound heterozygous state in a patient with mismatch repair cancer syndrome (MMRCS3; 619097) by Auclair et al. (2007), see 600678.0016. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000257247.2 First in ClinVar: Nov 20, 2015 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: SCV000592632.2 First in ClinVar: Oct 11, 2015 Last updated: Apr 13, 2021	Comment: The p.Phe1088SerfsX2 variant was identified in 15 of 6554 proband chromosomes (frequency: 0.002) from individuals or families with Lynch syndrome (Bonadona 2011, Devlin 2008, Hampel … (more) The p.Phe1088SerfsX2 variant was identified in 15 of 6554 proband chromosomes (frequency: 0.002) from individuals or families with Lynch syndrome (Bonadona 2011, Devlin 2008, Hampel 2005, Hendriks 2004, Overbeek 2007, Plaschke 2004, Sjursen 2010). The variant was also identified in dbSNP (ID: rs267608078) â€šÃ„ÃºWith pathogenic alleleâ€šÃ„Ã¹, Clinvitae database (2x as pathogenic), InSiGHT Colon Cancer Gene Variant Database (24x as pathogenic), the ClinVar database (classified as a pathogenic variant by an expert panel), GeneInsight COGR database 1x and UMD (27x as a causal variant). The p.Phe1088SerfsX2 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1088 and leads to a premature stop codon at position 1089. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MSH6 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. (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: SCV002758318.1 First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023	Publications: PubMed (1) PubMed: 36988593
Pathogenic (Feb 21, 2023)	no assertion criteria provided Method: clinical testing	Endometrial carcinoma Affected status: yes Allele origin: germline	CZECANCA consortium Accession: SCV003804329.1 First in ClinVar: Feb 25, 2023 Last updated: Feb 25, 2023	Number of individuals with the variant: 1 Ethnicity/Population group: Slavic Geographic origin: Czech Republic
not provided (-)	no classification provided Method: phenotyping only	Lynch syndrome 5 Affected status: unknown Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV002075254.1 First in ClinVar: Feb 12, 2022 Last updated: Feb 12, 2022	Comment: Variant interpreted as Pathogenic and reported on 03-09-2020 by Lab or GTR ID 1197. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more) Variant interpreted as Pathogenic and reported on 03-09-2020 by Lab or GTR ID 1197. 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: Abnormal delivery (present) , Abnormality of the umbilical cord (present) , Myopia (present) , Abnormal erythrocyte morphology (present) , Abnormal leukocyte morphology (present) , Neoplasm … (more) Abnormal delivery (present) , Abnormality of the umbilical cord (present) , Myopia (present) , Abnormal erythrocyte morphology (present) , Abnormal leukocyte morphology (present) , Neoplasm of uterus (present) , Periodontitis (present) , Gingivitis (present) (less) Age: 40-49 years Sex: female Testing laboratory: Myriad Genetic Laboratories, Inc.,Myriad Genetic Laboratories, Inc. Date variant was reported to submitter: 2020-03-09 Testing laboratory interpretation: Pathogenic
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Comment:

This variant alters the translational reading frame of the MSH6 mRNA and causes the premature termination of MSH6 protein synthesis. In the published literature, this variant has been reported in individuals affected with a Lynch syndrome associated cancer (PMIDs: 20028993 (2010), 20591884 (2010), 22734033 (2012), 26787237 (2016), 29371908 (2018)) and CMMRD (PMID: 32042422 (2020)). The frequency of this variant in the general population, 0.000014 (4/280876 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.

Comment:

This variant deletes 1 nucleotide in exon 5 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals and families affected with Lynch syndrome, Muir-Torre syndrome, or constitutional mismatch repair deficiency syndrome (PMID: 15236168, 15483016, 17117178, 17557300, 20007843, 20487569, 20587412, 22480969, 22734033, 27064304). This variant has been identified in 1/30714 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Phe1088Serfs*2) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 10508506, 15483016, 18301448, 20007843, 20028993, 20587412, 20591884, 22734033). ClinVar contains an entry for this variant (Variation ID: 89363). For these reasons, this variant has been classified as Pathogenic.

Comment:

The c.3261delC pathogenic mutation, located in coding exon 5 of the MSH6 gene, results from a deletion of one nucleotide at nucleotide position 3261, causing a translational frameshift with a predicted alternate stop codon (p.F1088Sfs*2). This mutation has been reported in multiple hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome families; several whose LS-associated tumors demonstrating high microsatellite instability and/or loss of MSH6 staining by immunohistochemistry (IHC) (Wijnen J et al. Nat. Genet. 1999 Oct;23:142-4; Kets CM et al. Br J Cancer, 2006 Dec;95:1678-82; Devlin LA et al. Ulster Med J, 2008 Jan;77:25-30; Talseth-Palmer BA et al. Hered. Cancer Clin. Pract. 2010 May;8:5; van der Post RS et al. J. Med. Genet. 2010 Jul;47:464-70; Bonnet D et al. Dig Liver Dis, 2012 Jun;44:515-22; Sjursen W et al. Mol Genet Genomic Med, 2016 Mar;4:223-31; Lagerstedt-Robinson K et al. Oncol Rep. 2016 Nov;36(5):2823-2835; Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43; Ylmaz A et al. Int J Colorectal Dis, 2020 Feb;35:351-353). This mutation has also been reported in the homozygous state as well as compound heterozygous with a second mutation in MSH6 in several patients with Constitutional Mismatch Repair Deficiency (CMMRD) syndrome (Auclair J et al. Hum Mutat. 2007 Nov;28(11):1084-90; Xu M et al. Biomed Rep, 2020 Mar;12:134-138; Ando T et al. BMC Gastroenterol, 2021 Aug;21:326). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

Comment:

Variant summary: The MSH6 c.3261delC (p.Phe1088Serfs) variant results in a premature termination codon, predicted to cause a truncated or absent MSH6 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Arg1172fs). One in silico tool predicts a damaging outcome for this variant. This variant was found in 21/120336 control chromosomes at a frequency of 0.0001745, which is approximately equal to the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). However, the variant has been reported in many HNPCC patients in the literature in heterozygous state. The variant has also been cited in homozygous and compound heterozygous states in patients with early onset cancer phenotypes (Ilencikova_PedBlodCanc_2011 and Auclair_HumMut_2007, respectively). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

Comment:

The MSH6 c.3261delC, p.Phe1088fs variant (rs267608078) is a recurrent alteration in individuals diagnosed with hereditary nonpolyposis colorectal cancer and other familial cancers (Baglietto 2010, Lavoine 2015, Tavakkol 2012, van der Post 2010, Wijnen 1999). It is classified as pathogenic in ClinVar (Variation ID: 89363), and observed once in the Genome Aggregation Database general population database (1/30714 alleles). The variant introduces a frameshift, and is predicted to result in a truncated protein or an absent transcript. Based on the above information, the variant is classified as pathogenic. References: Baglietto L et al. Risks of Lynch syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst. 2010; 102(3):193-201. Lavoine N et al. Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort. J Med Genet. 2015; 52(11):770-8. Tavakkol Z et al. Germline mutation in MSH6 associated with multiple malignant neoplasms in a patient With Muir-Torre syndrome. J Clin Oncol. 2012; 30(22):e195-8. van der Post R et al. Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers. J Med Genet. 2010; 47(7):464-70. Wijnen J et al. Familial endometrial cancer in female carriers of MSH6 germline mutations. Nat Genet. 1999; 23(2):142-4.

Comment:

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek 2016); Observed in the heterozygous state in patients with Lynch-related cancers consistent with pathogenic variants in this gene (Plaschke 2004, Hampel 2005, Baglietto 2010, Sjursen 2010, Talseth-Palmer 2010, Meric-Bernstam 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 26552419, 26787237, 15872200, 29371908, 20591884, 20028993, 15483016, 20487569, 20587412, 26866578, 27601186, 27486176, 25980754, 10508506, 22734033, 26681312, 28528517, 26318770, 30730459, 30322717, 30093976, 31447099, 31845022, 31921681, 32832836, 32042422, 17557300, 32719484, 30787465, 33087929)

Comment:

The p.Phe1088SerfsX2 variant in MSH6 has been reported in the heterozygous state in >5 individuals with MSH6-associated cancers (Baglietto 2010 PMID: 20028993, Meric-Bernstam 2016 PMID: 26787237), and in the compound heterozygous state in 1 individual with constitutional mismatch repair deficiency syndrome (CMMRD) who also carried another MSH6 variant (Lavoine 2015 PMID: 26318770). This variant has been identified in 0.01% (1/10370) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). It is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1088 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of function of the MSH6 gene is an established disease mechanism in Lynch Syndrome. Furthermore, this variant was classified as Pathogenic on Sept. 5, 2013 by the ClinGen-approved InSiGHT Expert Panel (ClinVar Variation ID: 89363). In summary, this variant meets criteria to be classified as pathogenic for Lynch Syndrome in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4_Supporting, PM2_Supporting, PVS1.

Comment:

This variant deletes 1 nucleotide in exon 5 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome, Muir-Torre syndrome and constitutional mismatch repair deficiency syndrome (PMID: 15236168, 15483016, 17117178, 17557300, 20007843, 20487569, 20587412, 22480969, 22734033, 27064304). This variant has been identified in 1/30714 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

Comment:

The p.Phe1088SerfsX2 variant was identified in 15 of 6554 proband chromosomes (frequency: 0.002) from individuals or families with Lynch syndrome (Bonadona 2011, Devlin 2008, Hampel 2005, Hendriks 2004, Overbeek 2007, Plaschke 2004, Sjursen 2010). The variant was also identified in dbSNP (ID: rs267608078) â€šÃ„ÃºWith pathogenic alleleâ€šÃ„Ã¹, Clinvitae database (2x as pathogenic), InSiGHT Colon Cancer Gene Variant Database (24x as pathogenic), the ClinVar database (classified as a pathogenic variant by an expert panel), GeneInsight COGR database 1x and UMD (27x as a causal variant). The p.Phe1088SerfsX2 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1088 and leads to a premature stop codon at position 1089. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MSH6 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic.

Comment:

Variant interpreted as Pathogenic and reported on 03-09-2020 by Lab or GTR ID 1197. 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.

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:

This variant deletes 1 nucleotide in exon 5 of the MSH6 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome, Muir-Torre syndrome and constitutional mismatch repair deficiency syndrome (PMID: 15236168, 15483016, 17117178, 17557300, 20007843, 20487569, 20587412, 22480969, 22734033, 27064304). This variant has been identified in 1/30714 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

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
Intensive surveillance endoscopy for multiple gastrointestinal tumors in a patient with constitutional mismatch repair deficiency: case report.	Ando T	BMC gastroenterology	2021	PMID: 34425783
Exome sequencing and characterization of 49,960 individuals in the UK Biobank.	Van Hout CV	Nature	2020	PMID: 33087929
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
Diagnosis of a case of homozygous constitutional MMR-deficiency by the use of a gene-panel in a non-consanguineous family: A case report.	Xu M	Biomedical reports	2020	PMID: 32042422
Diagnostic yield of a custom-designed multi-gene cancer panel in Irish patients with breast cancer.	McVeigh ÚM	Irish journal of medical science	2020	PMID: 32008151
Colorectal cancer in Lynch syndrome associated with PMS2 and MSH6 mutations.	Yılmaz A	International journal of colorectal disease	2020	PMID: 31845022
Latin American Study of Hereditary Breast and Ovarian Cancer LACAM: A Genomic Epidemiology Approach.	Oliver J	Frontiers in oncology	2019	PMID: 31921681
Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network.	eMERGE Consortium. Electronic address: [email protected]	American journal of human genetics	2019	PMID: 31447099
Toward automation of germline variant curation in clinical cancer genetics.	Ravichandran V	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 30787465
Detection of Pathogenic Germline Variants Among Patients With Advanced Colorectal Cancer Undergoing Tumor Genomic Profiling for Precision Medicine.	You YN	Diseases of the colon and rectum	2019	PMID: 30730459
Germline pathogenic variants identified in women with ovarian tumors.	Carter NJ	Gynecologic oncology	2018	PMID: 30322717
Clinical genetic testing outcome with multi-gene panel in Asian patients with multiple primary cancers.	Chan GHJ	Oncotarget	2018	PMID: 30093976
Genetic variants of prospectively demonstrated phenocopies in BRCA1/2 kindreds.	Dominguez-Valentin M	Hereditary cancer in clinical practice	2018	PMID: 29371908
Lynch syndrome mutation spectrum in New South Wales, Australia, including 55 novel mutations.	Sjursen W	Molecular genetics & genomic medicine	2016	PMID: 27064304
Incidental germline variants in 1000 advanced cancers on a prospective somatic genomic profiling protocol.	Meric-Bernstam F	Annals of oncology : official journal of the European Society for Medical Oncology	2016	PMID: 26787237
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
Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort.	Lavoine N	Journal of medical genetics	2015	PMID: 26318770
Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.	Thompson BA	Nature genetics	2014	PMID: 24362816
Germline mutation in MSH6 associated with multiple malignant neoplasms in a patient With Muir-Torre syndrome.	Tavakkol Z	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2012	PMID: 22734033
Simplified identification of Lynch syndrome: a prospective, multicenter study.	Bonnet D	Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver	2012	PMID: 22480969
High-grade brain tumors in siblings with biallelic MSH6 mutations.	Ilencikova D	Pediatric blood & cancer	2011	PMID: 21674763
Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers.	van der Post RS	Journal of medical genetics	2010	PMID: 20591884
Current clinical criteria for Lynch syndrome are not sensitive enough to identify MSH6 mutation carriers.	Sjursen W	Journal of medical genetics	2010	PMID: 20587412
MSH6 and PMS2 mutation positive Australian Lynch syndrome families: novel mutations, cancer risk and age of diagnosis of colorectal cancer.	Talseth-Palmer BA	Hereditary cancer in clinical practice	2010	PMID: 20487569
Risks of Lynch syndrome cancers for MSH6 mutation carriers.	Baglietto L	Journal of the National Cancer Institute	2010	PMID: 20028993
Combined iPLEX and TaqMan assays to screen for 45 common mutations in Lynch syndrome and FAP patients.	Dymerska D	The Journal of molecular diagnostics : JMD	2010	PMID: 20007843
Screening for germline mutations of MLH1, MSH2, MSH6 and PMS2 genes in Slovenian colorectal cancer patients: implications for a population specific detection strategy of Lynch syndrome.	Berginc G	Familial cancer	2009	PMID: 19526325
No association between MUTYH and MSH6 germline mutations in 64 HNPCC patients.	Steinke V	European journal of human genetics : EJHG	2008	PMID: 18301448
Germline MSH6 mutations are more prevalent in endometrial cancer patient cohorts than hereditary non polyposis colorectal cancer cohorts.	Devlin LA	The Ulster medical journal	2008	PMID: 18269114
Novel biallelic mutations in MSH6 and PMS2 genes: gene conversion as a likely cause of PMS2 gene inactivation.	Auclair J	Human mutation	2007	PMID: 17557300
Very low prevalence of germline MSH6 mutations in hereditary non-polyposis colorectal cancer suspected patients with colorectal cancer without microsatellite instability.	Kets CM	British journal of cancer	2006	PMID: 17117178
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
Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: impact on counseling and surveillance.	Hendriks YM	Gastroenterology	2004	PMID: 15236168
Familial endometrial cancer in female carriers of MSH6 germline mutations.	Wijnen J	Nature genetics	1999	PMID: 10508506
http://www.insight-database.org/classifications/index.html?gene=MSH6&variant=c.3261del	-	-	-	-
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Text-mined citations for rs267608078 ...

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 Jan 13, 2025

ClinVar Genomic variation as it relates to human health

NM_000179.3(MSH6):c.3261del (p.Phe1088fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs267608078 ...