ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.866_867delinsAA (p.Gly289Glu) (rs267608079)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000524216 SCV000166238 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-27 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 289 of the MSH6 protein (p.Gly289Glu). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is present in population databases (rs267608079, ExAC 0.006%). This variant has been observed in individuals affected with colorectal and/or endometrial cancer (PMID: 16010685, 18269114, 20028993). ClinVar contains an entry for this variant (Variation ID: 89572). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), and an algorithm developed specifically for MSH6 (PMID: 23621914), suggest that this missense change is likely to be tolerated, although these predictions have not been confirmed by published functional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000129540 SCV000184318 likely benign Hereditary cancer-predisposing syndrome 2019-10-01 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification;Structural Evidence
GeneDx RCV000235182 SCV000211382 likely benign not specified 2018-01-08 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Counsyl RCV000411287 SCV000488194 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-01-22 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000235182 SCV000712574 uncertain significance not specified 2016-11-15 criteria provided, single submitter clinical testing The p.Gly289Glu variant in MSH6 has been classified as a variant of uncertain si gnificance on September 5, 2013 by the ClinGen-approved InSiGHT Expert Panel (Cl inVar SCV000108262.2). It has been reported in 2 individuals with Lynch syndrome associated tumors (Colley 2005, Devlin 2008) and is present in 4/66588 of Europ ean chromosomes in the Exome Aggregation Consortium database (ExAC, http://exac., note that the ExAC database reports this variant as 2 separa te substitutions in cis, c.866G>A [rs267608079] and c.867C>A [rs267608047]). Com putational prediction tools and conservation analysis are limited or unavailable for this variant. In summary, the clinical significance of the p.Gly289Glu vari ant is uncertain.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000411287 SCV000781784 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-11-01 criteria provided, single submitter clinical testing
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000761154 SCV000891070 uncertain significance Lynch syndrome 2020-10-22 criteria provided, single submitter clinical testing The MSH6 c.866_867delinsAA (p.Gly289Glu) variant is absent in gnomAD v2.1.1 (PM2_Supporting). An in silico tool developed for MSH6, CoDP, predicts a benign effect of this variant on protein function (BP4; PMID: 23621914), but this prediction has not been confirmed by functional studies. This variant has been reported in a family with Lynch syndrome (PMID: 20028993), and in individuals with endometrial cancer (PMID: 18269114) and breast cancer (PMID: 26898890). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_Supporting, BP4.
Color Health, Inc RCV000129540 SCV000910638 likely benign Hereditary cancer-predisposing syndrome 2016-01-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000235182 SCV000919740 uncertain significance not specified 2018-09-28 criteria provided, single submitter clinical testing Variant summary: MSH6 c.866_867delinsAA (p.Gly289Glu) results in a non-conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00003302 in 121128 control chromosomes (ExAC). This frequency is not significantly higher than expected for a pathogenic variant in MSH6 causing Lynch Syndrome (0.00003302 vs 0.00014), allowing no conclusion about variant significance. The variant, c.866_867delinsAA, has been reported in the literature in individuals affected with HNPCC, colorectal adenomas, colorectal and breast cancer (Colley_2005, Devlin_2008, Baglietto_2010, Caminsky_2016). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS x5, likely benign x1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985852 SCV001134458 uncertain significance not provided 2019-03-19 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000761154 SCV000592577 uncertain significance Lynch syndrome no assertion criteria provided clinical testing The p.Gly289Glu variant has been previously reported in the literature in 2/880 proband chromosomes. One individual had multiple colorectal adenomas and the other had HNPCC (Colley 2005, Devlin 2008). However, race-matched population controls were not sequenced in these studies and so it is possible that the full spectrum of benign variation has not yet been defined for this gene, and this variant may be benign. This variant was identified by our laboratory in one individual who had normal IHC for MSH6 and was microsatellite stable increasing the likelihood this variant does not have clinical significance. The p.Gly289 residue is not conserved across mammals and lower species increasing the likelihood that this is a benign variant. In summary, based on the above information, the clinical significance of this variant cannot be determined at this time. Therefore, this variant is classified as a variant of unknown significance.

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