Submissions for variant NM_000179.3(MSH6):c.2057G>A (p.Gly686Asp)

gnomAD frequency: 0.00001  dbSNP: rs587779227

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074709	SCV000107916	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Multifactorial likelihood analysis posterior probability 0.95-0.99
Ambry Genetics	RCV000128865	SCV000172722	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-05	criteria provided, single submitter	clinical testing	The p.G686D pathogenic mutation (also known as c.2057G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 2057. The glycine at codon 686 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been identified in individuals who met Amsterdam II criteria for Lynch syndrome and one proband was reportedly diagnosed with rectal adenocarcinoma characterized by microsatellite instability as well as isolated loss of MSH6 protein expression on immunohistochemistry (IHC) (Ambry internal data; Buchanan DD et al. J. Gastroenterol. Hepatol., 2017 Feb;32:427-438). In addition, p.G686D has been identified in multiple individuals with Lynch syndrome-associated cancers undergoing multi-gene panel testing (Yurgelun MB et al. Gastroenterology. 2015 May. pii: S0016-5085(15)00678-2; DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569; Roberts ME et al. Genet. Med., 2018 10;20:1167-1174). In a study that quantified tumor characteristics to assess pathogenicity for germline mismatch repair gene variants, this variant was reported in individuals with Lynch syndrome-associated tumors that demonstrated isolated loss of MSH6 protein expression on IHC (Ambry internal data; Li S et al. J. Med. Genet., 2020 Jan;57:62-69). Functional analyses of G686D suggest this alteration abrogates mismatch repair activity (Houlleberghs H et al. PLoS Genet., 2017 May;13:e1006765). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well 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.
GeneDx	RCV000212657	SCV000211288	pathogenic	not provided	2023-04-27	criteria provided, single submitter	clinical testing	Observed in patients with Lynch-related cancers, many with tumor studies consistent with pathogenic variants in this gene (Hampel et al., 2008; Goodfellow et al., 2015; Yurgelun et al., 2015; Chubb et al., 2016; Buchanan et al., 2017); Published functional studies demonstrate a damaging effect: defective mismatch binding and MMR activity (Houlleberghs et al., 2017; Drost et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22949379, 25980754, 26552419, 18809606, 27329137, 17531815, 21120944, 24362816, 28531214, 27273229, 31965077, 25559809, 28514183, 28944238, 26681312, 30787465, 33087929, 28888541)
Invitae	RCV000524130	SCV000218884	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 686 of the MSH6 protein (p.Gly686Asp). 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 and/or constitutional mismatch repair deficiency syndrome (PMID: 18809606, 22949379, 25559809, 26552419, 26681312, 27273229, 28514183, 28944238; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 89245). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MSH6 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects MSH6 function (PMID: 28531214, 31965077). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212657	SCV000601526	pathogenic	not provided	2022-11-04	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000013 (2/152172 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with In the published literature, the variant has been reported in individuals with Lynch Syndrome or a Lynch Syndrome associated phenotype (PMID: 28944238 (2017), PMID: 28514183 (2017), PMID: 26552419 (2015), PMID: 25980754 (2015), PMID: 25559809 (2015), PMID: 18809606 (2008)). Additionally, this variant was found to abrogate MMR activity in vitro (PMID: 28531214 (2017)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
Counsyl	RCV000576301	SCV000677747	likely pathogenic	Lynch syndrome 5	2017-05-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001526863	SCV000917787	pathogenic	Hereditary nonpolyposis colon cancer	2021-06-03	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.2057G>A (p.Gly686Asp) results in a non-conservative amino acid change located in the connector domain (IPR007860) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251270 control chromosomes (gnomAD). c.2057G>A has been reported in the literature in multiple individuals affected with colorectal cancer (Hampel _2008, Thompson_ 2013, Chubb_2015, DeRycke_2017, Buchanan_2016), in patients with a history of LS-associated cancer and/or colorectal polyps (Yurgelun_2015, Li_2020) endometrial (Goodfellow_2015) and breast cancer (Susswein 2016). Tumor samples showed microsatellite instability in several cases (Chubb_2015, Buchanan_2016, Goodfellow_2015). These data indicate that the variant may be associated with disease. In addition, a multifactorial likelihood analysis classified this MSH6 variant as likely pathogenic (Thompson_2014). A recent functional study demonstrated reduced MMR activity for the variant compared to wild type (Drost_2020). Six other ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic (n=4) and pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000212657	SCV002023524	pathogenic	not provided	2022-12-19	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000576301	SCV002761770	likely pathogenic	Lynch syndrome 5	2022-03-24	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000576301	SCV004018984	pathogenic	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 28531214]. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 25085752].
Baylor Genetics	RCV001353773	SCV004195669	likely pathogenic	Endometrial carcinoma	2023-07-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000128865	SCV004357629	pathogenic	Hereditary cancer-predisposing syndrome	2022-10-10	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with aspartic acid at codon 686 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). DNA mismatch repair and DNA damage tolerance assays have shown that this variant reduces protein function (PMID: 28531214, 31965077). This variant has been reported in individuals affected with Lynch syndrome or suspected of having Lynch syndrome (PMID: 25980754, 25559809, 26552419, 26552419, 27273229), colorectal cancer (PMID: 18809606, 22949379, 28944238), or breast cancer (PMID: 26681312). 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 Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000074709	SCV004848293	likely pathogenic	Lynch syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The p.Gly686Asp variant in MSH6 has been reported in at least 5 individuals with Lynch syndrome (Yurgelun 2015, Goodfellow 2015, Thompson 2013, Hampel 2008, DeRycke 2017) and in 1 individual with breast cancer, who also carried a likely pathogenic variant in CHEK2 (Susswein 2016). It was absent from large population studies. This variant was classified as likely pathogenic on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 89245) and several clinical labs. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, and in vitro and in vivo (patient tumor) functional studies provide further evidence that this variant impacts protein function (Houlleberghs 2017, Goodfellow 2015, Thompson 2013). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PM2, PS4_Moderate, PS3_Moderate, PP3.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353773	SCV000592594	pathogenic	Endometrial carcinoma		no assertion criteria provided	clinical testing	The p.Gly686Asp variant was identified in 1 of 226 proband chromosomes (frequency: 0.004) from individuals or families with colorectal cancers (Hampel 2008). The variant was not identified in dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) databases. The variant was identified in Insight Colon Cancer Database (1x classified as likely pathogenic) and in Clinvitae (2x as likely pathogenic). In the ClinVar database, the variant was reported as likely pathogenic by Insight, Ambry Genetics, and GeneDX; Invitae classified the variant as of uncertain significance. The p.Gly686 residue is conserved across mammals but not in all other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, BLOSUM, MutationTaster) suggest that the Aspartic Acid variant may impact the protein. In silico splicing analysis suggests that this variant leads to creation of a cryptic 5’ donor splice site in 4 out 5 programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, Human Splicing Finder). However, this information is not predictive enough to assume pathogenicity. In addition, a multifactorial analysis study (Thompson 2013) concluded that the variant was likely pathogenic (posterior probability 0.95-0.99). This variant has been previously seen by our laboratory in one family with Lynch syndrome. In this family the variant was identified in four affected members, there are two affected obligate carries, across 2 generations, for a total of 6 dominant segregations. The four variant positive family members had MSH6 deficient tumors, although one of these tumors was deficient for MLH1, MSH2 and PMS2 as well. The cancers in the family include ureter, endometrial and skin cancer however one obligate carrier was reported to have skin cancer which has not been confirmed with medical documentation. We cannot rule out the possibility that the cancer in this family is due to a separate pathogenic variant that is also tracking with the disease. However, at least one family member with this variant had complete sequencing (by Sanger) and deletion duplication analysis (by MLPA) for the MLH1, MSH2 (EPCAM del/dup) and MSH6 genes which did not identify other causal variants. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000583928	SCV000691928	uncertain significance	not specified		no assertion criteria provided	clinical testing