ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1968C>A (p.Tyr656Ter) (rs63751317)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491519 SCV000580452 pathogenic Hereditary cancer-predisposing syndrome 2014-11-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other acmg-defined mutation (i.e. initiation codon or gross deletion)
GeneDx RCV000482698 SCV000567294 pathogenic not provided 2015-07-20 criteria provided, single submitter clinical testing This pathogenic variant is denoted MSH2 c.1968C>A at the cDNA level and p.Tyr656Ter (Y656X) at the protein level. The substitution creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAC>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in at least one individual with a personal and/or family history suspicious for Lynch syndrome (Yurgelun 2015). In addition, different nucleotide substitutions resulting in the same nonsense variant, MSH2 Tyr656Ter, have also been reported in families with clinical histories suspicious for Lynch syndrome (Kohonen-Corish 1996, Scott 2001, Taylor 2003, Mangold 2005, Kurzawski 2006, Loizidou 2014). we consider this variant to be pathogenic.
Invitae RCV000791741 SCV000931002 pathogenic Hereditary nonpolyposis colon cancer 2018-09-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr656*) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual suspected with Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 419473). A different variant (c.1968C>G) giving rise to the same protein effect observed here (p.Tyr656*) has been observed in individuals and families with clinical features of Lynch syndrome (PMID: 25133505, 8808596, 15849733, 28449805). Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). For these reasons, this variant has been classified as Pathogenic.

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