Submissions for variant NM_000179.3(MSH6):c.1190A>G (p.Tyr397Cys)

gnomAD frequency: 0.00001  dbSNP: rs63750065

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656894	SCV000211275	uncertain significance	not provided	2023-09-18	criteria provided, single submitter	clinical testing	Observed in at least two patients with a personal and family history of colorectal cancer, with one of these colon tumors exhibiting microsatellite instability (MSI) and loss of MLH1 and PMS2 proteins, and also observed in individuals with biliary, breast, or pancreatic cancer (Terui et al., 2013; Chubb et al., 2015; Terashima et al., 2019; Bono et al., 2021; Dorling et al., 2021; Hu et al., 2022; Yin et al., 2022); 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: 10675480, 24100870, 25559809, 23621914, 33471991, 17531815, 21120944, 31666926, 25085752, 24362816, 34371384, 35449176, 35171259, 36243179)
Invitae	RCV000206352	SCV000260423	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000565934	SCV000673925	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-11	criteria provided, single submitter	clinical testing	The p.Y397C variant (also known as c.1190A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 1190. The tyrosine at codon 397 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been identified in a patient who had a personal and family history of colorectal cancer (Chubb D et al. J. Clin. Oncol. 2015 Feb; 33(5):426-32), a patient with microsatellite unstable colorectal carcinoma showing loss of expression of the MLH1 and PMS2 proteins (Terui H et al. Oncol Rep, 2013 Dec;30:2909-16), and a cohort of patients diagnosed with biliary tract carcinoma undergoing multigene panel testing for hereditary cancer risk (Terashima T et al. Oncotarget, 2019 Oct;10:5949-5957). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000662428	SCV000784881	uncertain significance	Lynch syndrome 5	2017-01-25	criteria provided, single submitter	clinical testing
Mendelics	RCV000708864	SCV000837879	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656894	SCV000889455	uncertain significance	not provided	2020-02-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000565934	SCV000903473	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 397 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 individuals affected with colorectal cancer, with a tumor sample from one case showing microsatellite instability and loss of MLH1 and PMS2 proteins by immunohistochemistry (PMID: 24100870, 25559809), as well as in individuals affected with biliary tract, breast, ovarian, and pancreatic cancers (PMID: 27153395, 31666926, 32980694, 33471991, 34371384). The variant was also observed in healthy controls in a large pancreatic case-control study (PMID: 32980694). This variant has been identified in 6/251150 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000160665	SCV000917783	uncertain significance	not specified	2024-02-01	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1190A>G (p.Tyr397Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251150 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1190A>G has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer, intrahepatic bile duct cancer, pancreatic cancer and breast cancer (e.g. Chubb_2015, Terui_2013, Terashima_2019, Yin_2022, Hu_2022). It has also been reported in five breast cancer cases by a large study in the Breast Cancer Association Consortium (Dorling_2021) but was absent in the cohort of Biliary tract cancer by another large case-control study in Japan (Okawa_2023).These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34371384, 25559809, 35449176, 36243179, 31666926, 23621914, 24100870, 24362816, 35171259, 33471991). ClinVar contains an entry for this variant (Variation ID: 182620). Based on the evidence outlined above, the variant was classified as uncertain significance.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000160665	SCV000967446	uncertain significance	not specified	2018-10-16	criteria provided, single submitter	clinical testing	The p.Tyr397Cys variant in MSH6 has been reported in 2 individuals with colorect al cancer (Terui 2013, Chubb 2015) and has been reported by other clinical labor atories in ClinVar (Variation ID: 182620). This variant has also been identified in 2/30780 South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org) . Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. However, an algorithm develope d for in silico prediction of variants in MSH6 gene suggests that this variant i s likely to impact MSH6 function (Terui 2013). In summary, the clinical signific ance of the p.Tyr397Cys variant is uncertain. ACMG/AMP criteria applied: PS4_Sup porting, PM2_Supporting.
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030492	SCV001193646	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000565934	SCV002535612	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-23	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002484997	SCV002783166	uncertain significance	Endometrial carcinoma; Lynch syndrome 5; Mismatch repair cancer syndrome 3	2021-12-27	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000656894	SCV003808959	uncertain significance	not provided	2022-03-31	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662428	SCV004019049	likely benign	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
All of Us Research Program, National Institutes of Health	RCV000708864	SCV004843137	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 397 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 individuals affected with colorectal cancer, with a tumor sample from one case showing microsatellite instability and loss of MLH1 and PMS2 proteins by immunohistochemistry (PMID: 24100870, 25559809), as well as in individuals affected with biliary tract, breast, ovarian, and pancreatic cancers (PMID: 27153395, 31666926, 32980694, 33471991, 34371384). The variant was also observed in healthy controls in a large pancreatic case-control study (PMID: 32980694). This variant has been identified in 6/251150 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.