Submissions for variant NM_000179.3(MSH6):c.3469G>T (p.Gly1157Cys)

dbSNP: rs587779264

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132174	SCV000187253	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-07	criteria provided, single submitter	clinical testing	The p.G1157C pathogenic mutation (also known as c.3469G>T), located in coding exon 6 of the MSH6 gene, results from a G to T substitution at nucleotide position 3469. The glycine at codon 1157 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in several individuals whose Lynch-associated tumor demonstrated high microsatellite instability (MSI-H) and/or isolated loss of MSH6 protein expression on immunohistochemistry (IHC) (Ambry internal data). Based on an internal structural assessment, this alteration disrupts the local structure in the ATPase domain (Warren JJ et al. Mol. Cell. 2007 May;26:579-92). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000541079	SCV000624872	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 1157 of the MSH6 protein (p.Gly1157Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Lynch syndrome (internal data). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH6 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MSH6 testing. ClinVar contains an entry for this variant (Variation ID: 142773). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt MSH6 function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000132174	SCV000685408	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-12-28	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with cysteine at codon 1157 in the ATPase domain 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 observed in multiple individuals affected with Lynch syndrome-associated cancers (ClinVar submission ID: SCV000624872.7, SCV001446378.1 and SCV000187253.6). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant at this position, p.Gly1157Asp, has been reported to impact MSH6 function in DNA mismatch binding, in vitro mismatch repair and sensitivity to 6-thioguanine assays (PMID: 31965077). Three different amino acid substitutions, aspartic acid, serine and valine, in place of glycine 1157, have been observed in individuals affected with Lynch syndrome-associated cancers (PMID: 24323032, 31391288; Color internal data). These data indicate that glycine at this position is important for MSH6 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005237573	SCV001337984	pathogenic	Hereditary nonpolyposis colon cancer	2024-12-21	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3469G>T (p.Gly1157Cys) results in a non-conservative amino acid change located in the PWWP domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Another variant located at the same codon (c.3469G>A, p.Gly1157Ser) has been reported in individuals with MSH6-related consitions and/or colon cancer, supporting the critical relevance of this residue to MSH6 protein function. The variant was absent in 251390 control chromosomes. c.3469G>T has been reported in the literature in individuals with a personal and family history of Lynch Syndrome/Hereditary Nonpolyposis Colorectal Cancer (HNPCC) tested at our laboratory. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained (PMID: 28912153) although it was not captured as a case count in the context of this evaluation. ClinVar contains an entry for this variant (Variation ID: 142773). Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV002514752	SCV003194933	likely pathogenic	not provided	2023-10-18	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 17531815, 21120944, 28912153)
Baylor Genetics	RCV003462035	SCV004197745	likely pathogenic	Endometrial carcinoma	2023-09-08	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005031646	SCV005658589	likely pathogenic	Endometrial carcinoma; Lynch syndrome 5; Mismatch repair cancer syndrome 3	2024-03-28	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV001267890	SCV001446378	likely pathogenic	Lynch syndrome 5	2020-07-31	no assertion criteria provided	clinical testing