Submissions for variant NM_000179.3(MSH6):c.2731C>T (p.Arg911Ter)

gnomAD frequency: 0.00001  dbSNP: rs63751017

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074777	SCV000107987	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation resulting in a stop codon
Ambry Genetics	RCV000129807	SCV000184618	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-14	criteria provided, single submitter	clinical testing	The p.R911* pathogenic mutation (also known as c.2731C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 2731. This changes the amino acid from an arginine to a stop codon within coding exon 4. This mutation has been reported in multiple individuals and families diagnosed with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome (Goodfellow PJ et al. Proc. Natl. Acad. Sci. USA. 2003 May;100:5908-13; Hendriks YM et al. Gastroenterology. 2004 Jul;127:17-25; Plaschke J et al. J. Clin. Oncol. 2004 Nov;22:4486-94; Hampel H et al. Cancer Res. 2006 Aug;66:7810-7; Baglietto L et al. J. Natl. Cancer Inst. 2010 Feb;102:193-201; Palles C et al. Nat. Genet. 2013 Feb;45:136-44; Chubb D et al. J. Clin. Oncol. 2015 Feb;33:426-32; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Raskin L et al. Oncotarget. 2017 Nov;8:93450-93463). 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.
GeneDx	RCV000202017	SCV000211301	pathogenic	not provided	2022-07-12	criteria provided, single submitter	clinical testing	Nonsense 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24244552, 25117503, 29978187, 25525159, 23263490, 12732731, 15483016, 25637381, 15098177, 20487569, 23047549, 28176205, 26681312, 28873162, 20028993, 25559809, 16885385, 29212164, 15236168, 29760388, 29750335, 30521064, 31857677, 32242007, 31447099, 32081490, 31589614, 32719484, 30787465, 33087929, 34178123, 29130549)
Invitae	RCV000524149	SCV000261510	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg911*) 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). This variant is present in population databases (rs63751017, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with Lynch syndrome (PMID: 12732731, 15483016, 20487569, 23047549, 23263490). ClinVar contains an entry for this variant (Variation ID: 89312). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000411710	SCV000487951	pathogenic	Lynch syndrome 5	2015-12-06	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202017	SCV000601541	pathogenic	not provided	2020-11-06	criteria provided, single submitter	clinical testing	This nonsense variant is predicted to cause the premature termination of MSH6 protein synthesis. In the published literature, the variant has been reported in multiple individuals suspected of having Lynch syndrome in the published literature (PMIDs: 15236168 (2004), 23263490 (2013), 25117503 (2014), 26681312 (2015), 28176205 (2017), 29212164 (2017), 29978187 (2018), 30521064 (2019), 31857677 (2020), 32242007 (2020)). Based on the available information, this variant is classified as likely pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000129807	SCV000685320	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-18	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 4 of the MSH6 gene, creating a 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 observed in individuals affected with colorectal, ovarian, endometrial, small bowel and prostate cancer (PMID: 12732731, 15483016, 16885385, 19723918, 20587412, 25117503, 25559809, 26681312, 28176205, 29212164, 32081490, 32941469), in families affected with Lynch syndrome (PMID: 15236168, 20028993, 20487569, 23263490), and an individual affected with uveal melanoma (PMID: 32081490). This variant has been identified in 1/31398 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271398	SCV000695825	pathogenic	Hereditary nonpolyposis colon cancer	2022-06-08	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.2731C>T (p.Arg911X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant was absent in 250878 control chromosomes. c.2731C>T has been reported in the literature in multiple individuals affected with Hereditary Nonpolyposis Colorectal Cancer and endometrial cancer (e.g. Goodfellow_2003, Hendricks_2004, Plasche_2004, Hampel_2006, Talseth-Palmer_2010). These data indicate that the variant is very likely to be associated with disease. Thirteen ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000411710	SCV000744293	pathogenic	Lynch syndrome 5	2017-05-31	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000411710	SCV000840013	pathogenic	Lynch syndrome 5	2017-11-26	criteria provided, single submitter	clinical testing	The c.2731C>T (p.Arg911*) variant in the MSH6 gene is predicted to introduce a premature translation stop codon. This variant has been reported in the literature in multiple individuals with ovarian, colorectal, or prostate cancer (PMID: 12732731, 23047549, 23263490, 15236168, 15483016, 25117503, 16885385). The c.2731C>T (p.Arg911*) variant in the MSH6 gene is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000202017	SCV000884139	pathogenic	not provided	2017-09-08	criteria provided, single submitter	clinical testing	The MSH6 c.2731C>T; p.Arg911Ter variant (rs63751017) has previously been described in individuals and families with Lynch syndrome (Goodfellow 2003, Pal 2012, Plaschke 2004, Rosty 2014, Talseth-Palmer 2010). It is reported in the ClinVar database as pathogenic (Variation ID: 89312), and observed in the general population at a very low allele frequency of 0.008 percent (1/13006 alleles) in the Exome Variant Server, and 0.003 percent (1/30970 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or absent transcript. Based on the above information, this variant is considered pathogenic. REFERENCES Link to ClinVar database for p.Arg911Ter: https://www.ncbi.nlm.nih.gov/clinvar/variation/89312/ Goodfellow PJ et al. Prevalence of defective DNA mismatch repair and MSH6 mutation in an unselected series of endometrial cancers. Proc Natl Acad Sci U S A. 2003 May 13;100(10):5908-13. Pal T et al. Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer. Br J Cancer. 2012 Nov 6;107(10):1783-90. Plaschke J et al. 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. J Clin Oncol. 2004 Nov 15;22(22):4486-94. Rosty C et al. High prevalence of mismatch repair deficiency in prostate cancers diagnosed in mismatch repair gene mutation carriers from the colon cancer family registry. Fam Cancer. 2014 Dec;13(4):573-82. Talseth-Palmer BA et al. MSH6 and PMS2 mutation positive Australian Lynch syndrome families: novel mutations, cancer risk and age of diagnosis of colorectal cancer. Hered Cancer Clin Pract. 2010 May 21;8(1):5.
Fulgent Genetics, Fulgent Genetics	RCV002477210	SCV000894281	pathogenic	Endometrial carcinoma; Lynch syndrome 5; Mismatch repair cancer syndrome 3	2021-11-10	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000074777	SCV000967753	pathogenic	Lynch syndrome	2019-05-07	criteria provided, single submitter	clinical testing	The p.Arg911X variant in MSH6 has been reported in at least 13 individual with MSH6-associated cancers and segregated in at least 4 affected relatives (Goodfellow 2003, Buttin 2004, Hendriks 2004, Plaschke 2004, Hampel 2006, Talseth-Palmer 2010, Pal 2012, Palles 2013, Rosty 2014, Susswein 2015, Akbari 2017, Raskin 2017). This variant has also been reported in ClinVar (Variation ID 89312) and has been identified in 1/15426 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 911, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the MSH6 gene is an established disease mechanism in individuals with Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for Lynch syndrome in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1; PS4; PP1; PM2.
Revvity Omics, Revvity	RCV000202017	SCV002017590	pathogenic	not provided	2022-07-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129807	SCV002535764	pathogenic	Hereditary cancer-predisposing syndrome	2020-12-08	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000411710	SCV004018976	pathogenic	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
CeGaT Center for Human Genetics Tuebingen	RCV000202017	SCV004042072	pathogenic	not provided	2023-09-01	criteria provided, single submitter	clinical testing	MSH6: PVS1, PM2, PS4:Moderate
Baylor Genetics	RCV000148645	SCV004197585	pathogenic	Endometrial carcinoma	2023-10-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000074777	SCV004840805	pathogenic	Lynch syndrome	2023-11-28	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 4 of the MSH6 gene, creating a 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 observed in individuals affected with colorectal, ovarian, endometrial, small bowel and prostate cancer (PMID: 12732731, 15483016, 16885385, 19723918, 20587412, 25117503, 25559809, 26681312, 28176205, 29212164, 32081490, 32941469), in families affected with Lynch syndrome (PMID: 15236168, 20028993, 20487569, 23263490), and an individual affected with uveal melanoma (PMID: 32081490). This variant has been identified in 1/31398 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.
CSER _CC_NCGL, University of Washington	RCV000148645	SCV000190360	pathogenic	Endometrial carcinoma	2014-06-01	no assertion criteria provided	research
Mayo Clinic Laboratories, Mayo Clinic	RCV000202017	SCV000257227	pathogenic	not provided		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353531	SCV000592613	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Arg311* variant has been previously reported in the literature in at least 5 of 2738 proband chromosomes in individuals with Lynch syndrome related tumours and microsatellite instability (Selected publications: Plaschke 2004, Hendriks 2004, Hampel 2006, Goodfellow 2003). The p.Arg311* variant is predicted to cause a premature stop codon at position 311, which is then predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MSH6 gene are an established mechanism for Lynch syndrome and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant is classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000411710	SCV000734216	pathogenic	Lynch syndrome 5		no assertion criteria provided	clinical testing
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001554337	SCV001775551	pathogenic	Breast carcinoma	2021-08-10	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000202017	SCV001917110	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000202017	SCV001951251	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162471	SCV002758543	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research