ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1565_1568del (p.Tyr522fs) (rs1064793561)

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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 RCV000575960 SCV000662287 pathogenic Hereditary cancer-predisposing syndrome 2017-12-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000485928 SCV000566445 pathogenic not provided 2016-01-22 criteria provided, single submitter clinical testing The c.1565_1568delACTT pathogenic variant in the MSH2 gene has not been previously reported as a pathogenicvariant nor as a benign variant, to our knowledge. This variant causes a frameshift starting with codon Tyrosine 522,changes this amino acid to a Phenylalanine residue, and creates a premature Stop codon at position 3 of the newreading frame, denoted p.Tyr522PhefsX3. This variant is predicted to cause loss of normal protein function eitherthrough protein truncation or nonsense-mediated mRNA decay. The c.1565_1568delACTT variant was not observedin approximately 6500 individuals of European and African American ancestry in the NHLBI Exome SequencingProject, indicating it is not a common benign variant in these populations. Based on the ACMG recommendations,c.1565_1568delACTT is interpreted as an expected pathogenic sequence change.
Invitae RCV000629780 SCV000750736 pathogenic Hereditary nonpolyposis colon cancer 2017-10-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr522Phefs*3) 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 not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 418979). 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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