ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1696G>A (p.Gly566Arg) (rs63749973)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131251 SCV000186213 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-28 criteria provided, single submitter clinical testing The p.G566R variant (also known as c.1696G>A) is located in coding exon 4 of the MSH6 gene. This alteration results from a G to A substitution at nucleotide position 1696. The glycine at codon 566 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been observed to be linked in cis with the MSH6 alteration, p.A350V, and this haplotype has been identified in many individuals who do not have a personal or family history that is consistent with or suggestive of HNPCC/Lynch syndrome (Ambry internal data). This haplotype has also been identified in a homozygous state in an individual without characteristics of CMMRD (Ambry internal data). The p.G566R variant was detected in a patient with microsatellite unstable rectal cancer at age 62, which showed evidence of somatic MSH6 loss of heterozygosity (Kolodner RD et al. Cancer Res. 1999 Oct;59(20):5068-74). The authors found that p.G566R lead to a partial loss of MSH6 function in a yeast-based functional assay. In a second study, the p.G566R variant demonstrated intact MMR activity, but deficient MSH2-MSH6 interaction compared to wild type MSH6 (Kariola R et al. Hum. Mol. Genet. 2002 May;11(11):1303-10). A lack of attenuated MMR activity was also seen in another study that tested sensitivity to a DNA damaging agent and in an in vitro assay that analyzed microsatellite instability (Houlleberghs H et al. PLoS Genet., 2017 May;13:e1006765). Furthermore, heterodimer formation and stability was not affected for p.G566R in another study; however, significantly reduced MSH6 ATPase activity and reduced affinity for ATP was seen (Cyr JL and Heinen CS. J. Biol. Chem. 2008 Nov;283(46):31641-8). Based on protein sequence alignment, the p.G566 amino acid position is highly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000212651 SCV000211280 uncertain significance not provided 2020-02-21 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies are conflicting: reduced MMR activity, ATP binding, and ATPase activities (Kolodner 1999, Cyr 2008) but MMR activity and nuclear distribution pattern comparable to wild-type (Kariola 2002, Belvederesi 2012, Houlleberghs 2017); This variant is associated with the following publications: (PMID: 27899619, 22290698, 17594722, 22851212, 21120944, 12019211, 18790734, 15354210, 23621914, 26333163, 19766128, 10508506, 26269718, 28531214, 10537275, 31391288)
Invitae RCV001080487 SCV000219110 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-06 criteria provided, single submitter clinical testing
Counsyl RCV000411714 SCV000489717 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-11-11 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131251 SCV000685215 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-07 criteria provided, single submitter clinical testing This missense variant replaces glycine with arginine at codon 566 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 in yeast and using baculovirus expressed variant proteins have reported this variant protein to be unstable and defective in activity assays (PMID: 10537275, 12019211, 18790734). However, functional studies in mammalian cells indicated normal subcellular localization and rescue of sensitivity to DNA damage in MMR-deficient mouse cells (PMID: 22851212, 28531214). This variant has been reported in an individual affected with colorectal cancer (PMID: 10537275). This variant has been identified in 60/250316 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Mendelics RCV000411714 SCV001135810 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212651 SCV001469814 likely benign not provided 2020-07-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001328467 SCV001519615 likely benign not specified 2021-03-13 criteria provided, single submitter clinical testing Variant summary: MSH6 c.1696G>A (p.Gly566Arg) results in a non-conservative amino acid change located in the DNA mismatch repair protein MuT S, 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 allele was found at a frequency of 0.00024 in 250316 control chromosomes, predominantly at a frequency of 0.0015 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.1696G>A has been reported in the literature in at-least one non-HNPCC familial case in the population based series studied (Kolodner_1999). This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Several publications report conflicting experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a reduction of mismatch- stimulated ATPase activity (approx 11% of WT) despite normal ability of the protein to interact with MSH2 and a normal MSH6 nuclear import (example, Kariola_2002, Cyr_2008, Belvederesi_2012). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=2; VUS, n=5). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.

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