ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2906A>G (p.Tyr969Cys) (rs63749919)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000623975 SCV000740676 likely pathogenic Lynch syndrome I 2018-03-09 reviewed by expert panel curation Class 4 - Likely Pathogenic Classification using multifactorial probability: 0.9528
GeneDx RCV000218181 SCV000279613 likely pathogenic not provided 2017-04-20 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2906A>G at the cDNA level, p.Tyr969Cys (Y969C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT) in exon 4. This variant has been reported in at least three colorectal cancer families where loss of MSH6 has been observed via mismatch repair immunohistochemistry (MMR IHC) in several individuals' colon tumors (Suchy 2006, Grindedal 2009, Sjursen 2010). In addition, this variant is noted to segregate with cancer in at least two families (Grindedal 2009, Sjursen 2010). MSH6 Tyr969Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Tyr969Cys occurs at a position that is conserved in mammals and is located in the MutS IV domain (Terui 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence and internal data, we consider MSH6 Tyr969Cys to be a likely pathogenic variant.
Invitae RCV000458194 SCV000551056 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-08-18 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 969 of the MSH6 protein (p.Tyr969Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs63749919, ExAC 0.007%). This variant has been observed to segregate with Lynch syndrome in at least one family (PMID: 20587412, 16813607, 19723918). ClinVar contains an entry for this variant (Variation ID: 234622). General 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 the MSH6 gene (PMID: 23621914), suggest that this missense change is likely to be deletrious. However, these predictions have not been confirmed by published functional studies. 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.
Ambry Genetics RCV000491101 SCV000580279 likely pathogenic Hereditary cancer-predisposing syndrome 2020-01-16 criteria provided, single submitter clinical testing The p.Y969C variant (also known as c.2906A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 2906. The tyrosine at codon 969 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple families with Lynch syndrome with tumors exhibiting a loss of MSH6 staining on IHC (Suchy J et al. Clin Genet. 2006 Jul;70(1):68-70; Grindedal EM et al. Cancer Epidemiol. Biomarkers Prev. 2009 Sep;18(9):2460-7; Sjursen W et al. J. Med. Genet. 2010 Sep;47(9):579-85). This alteration has also been reported in an individual from a cohort of adult optic glioma patients (Sa JK et al. Int. J. Cancer. 2019 06;144:3023-3030). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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