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
Ambry Genetics RCV000128865 SCV000172722 likely pathogenic Hereditary cancer-predisposing syndrome 2018-03-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other data supporting pathogenic classification,Deficient protein function in appropriate functional assay(s)
Counsyl RCV000576301 SCV000677747 likely pathogenic Hereditary nonpolyposis colorectal cancer type 5 2017-05-11 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000074709 SCV000592594 pathogenic Lynch syndrome 2016-03-03 criteria provided, single submitter clinical testing
GeneDx RCV000212657 SCV000211288 likely pathogenic not provided 2017-08-23 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2057G>A at the cDNA level, p.Gly686Asp (G686D) at the protein level, and results in the change of a Glycine to an Aspartic Acid (GGT>GAT). This variant was observed in individuals with a personal and/or family history suspicious for Lynch syndrome (Hampel 2008, Goodfellow 2015, Yurgelun 2015). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as likely pathogenic based on their multifactorial likelihood analysis (Thompson 2013, Thompson 2014). Functional studies demonstrated that mouse embryonic stem cells with MSH6 Gly686Asp abrogated mismatch repair and demonstrated higher MSI levels in comparison to MMR proficient controls (Houlleberghs 2017). MSH6 Gly686Asp was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glycine and Aspartic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Gly686Asp occurs at a position where amino acids with properties similar to Glycine are tolerated across species and is located in the Connector domain (Warren 2007, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider MSH6 Gly686Asp to be a likely pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000074709 SCV000917787 likely pathogenic Lynch syndrome 2018-12-20 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 245984 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), 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). At least one publication reports experimental evidence evaluating an impact on protein function, demonstrating abrogated MMR activity in mouse embryonic stem cells (Houlleberghs 2017). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as likely pathogenic (6x) / pathogenic (1x). Based on the evidence outlined above, the variant was classified as likely pathogenic.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074709 SCV000107916 likely pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability 0.95-0.99
Invitae RCV000524130 SCV000218884 likely pathogenic Hereditary nonpolyposis colon cancer 2018-12-21 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 phenotypes 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). 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.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000583928 SCV000691928 uncertain significance not specified no assertion criteria provided clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212657 SCV000601526 pathogenic not provided 2018-03-08 criteria provided, single submitter clinical testing

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