ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1224T>G (p.Tyr408Ter) (rs63750132)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000569136 SCV000676100 pathogenic Hereditary cancer-predisposing syndrome 2019-03-27 criteria provided, single submitter clinical testing The p.Y408* pathogenic mutation (also known as c.1224T>G), located in coding exon 7 of the MSH2 gene, results from a T to G substitution at nucleotide position 1224. This changes the amino acid from a tyrosine to a stop codon within coding exon 7. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780440 SCV000917689 likely pathogenic Lynch syndrome 2018-02-20 criteria provided, single submitter clinical testing Variant summary: MSH2 c.1224T>G (p.Tyr408X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.1477C>T (p.Gln493X), c.1576delA (p.Thr526fsX17), and c.1705_1706delGA (p.Glu569fsX2)). The variant was absent in 246208 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1224T>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) classifies the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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