Submissions for variant NM_000179.3(MSH6):c.3577G>A (p.Glu1193Lys)

dbSNP: rs63751328

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166108	SCV000216875	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-08-07	criteria provided, single submitter	clinical testing	The p.E1193K variant (also known as c.3577G>A), located in coding exon 7 of the MSH6 gene, results from a G to A substitution at nucleotide position 3577. The glutamic acid at codon 1193 is replaced by lysine, an amino acid with similar properties. This alteration has been identified in two unrelated individuals diagnosed with endometrial cancer at ages 59 and 60, respectively, whose tumors showed high microsatellite instability (MSI-H) with loss of MSH6 staining on immunohistochemistry (IHC) (Kariola R et al. Br. J. Cancer, 2004 Oct;91:1287-92; Belvederesi L et al. Fam. Cancer. 2012 Dec;11:675-80). An in vivo mismatch repair (MMR) assay demonstrated that the E1193K variant displayed complete MMR deficiency at 0%. Additionally, a co-immunoprecipitation assay showed that the E1193K protein co-precipitated much less MSH2 compared to wildtype MSH6, suggesting interference in the heterodimerization between the MSH2 and MSH6 proteins (Kariola R et al. Br. J. Cancer. 2004 Oct;91:1287-92; Hampel H et al. Cancer Res. 2006 Aug;66:7810-7). In another study, the mouse equivalent of this variant was detected in a functional genetic screen and was shown to abrogate MMR activity (Houlleberghs H et al. PLoS Genet., 2017 May;13:e1006765). Based on an internal structural assessment, this alteration destabilizes the ATPase domain (Warren JJ et al. Mol. Cell, 2007 May;26:579-92). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
PreventionGenetics, part of Exact Sciences	RCV000679239	SCV000805895	likely pathogenic	not provided	2017-11-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001302789	SCV001492013	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-12-10	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1193 of the MSH6 protein (p.Glu1193Lys). 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 (PMID: 15354210, 16885385; external communication, internal data). ClinVar contains an entry for this variant (Variation ID: 89422). 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%. Experimental studies have shown that this missense change affects MSH6 function (PMID: 15354210, 28531214). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000166108	SCV002053487	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-11-09	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 1193 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). Functional studies have shown that this variant protein results in impaired DNA mismatch repair activity and reduced association with the MSH2 protein (PMID: 15354210). Another functional study has shown that the equivalent variant protein (p.Glu1191Lys) in mice also results in impaired DNA mismatch repair activity (PMID: 28531214). This variant has been reported in two individuals affected with endometrial cancer (PMID: 15354210, 16885385, 28531214), with microsatellite instability and/or loss of MSH6 protein expression reported in tumor samples. This variant has been reported in individuals affected with clinical features of Lynch syndrome (ClinVar SCV001492013.3). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230394	SCV003928831	likely pathogenic	Hereditary nonpolyposis colon cancer	2023-04-04	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3577G>A (p.Glu1193Lys) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal (IPR000432) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249974 control chromosomes. c.3577G>A has been reported in the literature in individuals affected with endometrial cancer showing microsatellite instability and loss of MSH6 expression (Kariola_2004, Hampel_2006). These data indicate that the variant is likely associated with disease. At least two publications reports experimental evidence evaluating an impact on protein function, showing a loss of MMR activity and disruption of heterodimerisation with MSH2 (Kariola_2004, Houlleberghs_2017). Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 , and all classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Myriad Genetics, Inc.	RCV003450974	SCV004187403	pathogenic	Lynch syndrome 5	2023-08-24	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 28531214, 15354210]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726].
Baylor Genetics	RCV003460687	SCV004198103	likely pathogenic	Endometrial carcinoma	2022-12-14	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997093	SCV004835096	likely pathogenic	Lynch syndrome	2024-01-08	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 1193 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). Functional studies have shown that this variant protein results in impaired DNA mismatch repair activity and reduced association with the MSH2 protein (PMID: 15354210). Another functional study has shown that the equivalent variant protein (p.Glu1191Lys) in mice also results in impaired DNA mismatch repair activity (PMID: 28531214). This variant has been reported in two individuals affected with endometrial cancer (PMID: 15354210, 16885385, 28531214), with microsatellite instability and/or loss of MSH6 protein expression reported in tumor samples. This variant has been reported in individuals affected with clinical features of Lynch syndrome (ClinVar SCV001492013.3). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.