ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1676G>A (p.Cys559Tyr) (rs63750595)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000215230 SCV000279612 uncertain significance not provided 2016-11-11 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1676G>A at the cDNA level, p.Cys559Tyr (C559Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGC>TAC). This variant was observed in an individual with endometrial and a family history of ovarian cancer (Suchy 2006). MSH6 Cys559Tyr 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 Cysteine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Cys559Tyr occurs at a position that is conserved in mammals and is located within the binding sites of MSH2 and domain II of the MutS domain (Kariola 2002, Terui 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Cys559Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000490883 SCV000580127 uncertain significance Hereditary cancer-predisposing syndrome 2014-08-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Moderate segregation with disease (at least 3 informative meioses) for rare diseases.,Insufficient or conflicting evidence

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