ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2057G>A (p.Gly686Asp) (rs587779227)

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Total submissions: 9
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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 2020-08-05 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 2020-03-17 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: defective mismatch binding and MMR activity (Houlleberghs 2017, Drost 2020); Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in patients with Lynch-related cancers, many with tumor studies consistent with pathogenic variants in this gene (Hampel 2008, Goodfellow 2015, Yurgelun 2015, Chubb 2016, Buchanan 2017); This variant is associated with the following publications: (PMID: 22949379, 25980754, 26552419, 18809606, 27329137, 17531815, 21120944, 24362816, 28531214, 27273229, 31965077, 25559809, 28514183, 28944238, 26681312)
Invitae RCV000524130 SCV000218884 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-10-16 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 686 of the MSH6 protein (p.Gly686Asp). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has reported in the literature in individuals with personal and family history of Lynch syndrome and/or colorectal cancer (PMID: 18809606, 22949379, 25559809, 28944238, 28514183) and individuals affected with endometrial and breast cancer (PMID: 26552419, 26681312). In addition, this variant has been observed as homozygous in an individual with clinical features consistent with autosomal recessive constitutional mismatch repair deficiency (CMMR-D) syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 89245). A multifactorial likelihood model which combined likelihood ratios for different pathogenic variant-associated characteristics, including segregation data from families and estimates of pathogenicity based on sequence conservation and position, classified this MSH6 variant as likely pathogenic (PMID: 24362816). An experimental study has shown that the missense change, p.Gly686Asp, representing p.Gly683Asp in the mouse MSH6 protein, abrogates MMR activity, reduces MSH6 and MSH2 expression and increases DNA polymerase slippage rates in a mouse ES cell model (PMID: 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212657 SCV000601526 pathogenic not provided 2018-03-08 criteria provided, single submitter clinical testing
Counsyl RCV000576301 SCV000677747 likely pathogenic Hereditary nonpolyposis colorectal cancer type 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.
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

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