ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.932del (p.Asn311fs) (rs587779979)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115548 SCV000149457 pathogenic not provided 2018-09-24 criteria provided, single submitter clinical testing This deletion of one nucleotide in MSH2 is denoted c.932delA at the cDNA level and p.Asn311ThrfsX20 (N311TfsX20) at the protein level. The normal sequence, with the base that is deleted in brackets, is CTTA[delA]CCTT. The deletion causes a frameshift which changes an Asparagine to a Threonine at codon 311, and creates a premature stop codon at position 20 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH2 c.932delA has been reported in at least one individual referred for clinical testing for inherited cancer (Susswein 2015). We consider this variant to be pathogenic.
Invitae RCV000232943 SCV000284196 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-11-25 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn311Thrfs*20) 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 with colon polyps (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 127655). Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000491121 SCV000580385 pathogenic Hereditary cancer-predisposing syndrome 2018-11-01 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000115548 SCV000889445 pathogenic not provided 2018-03-07 criteria provided, single submitter clinical testing
Color RCV000491121 SCV001354534 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193288 SCV001362023 pathogenic Hereditary nonpolyposis colon cancer 2019-06-13 criteria provided, single submitter clinical testing Variant summary: MSH2 c.932delA (p.Asn311ThrfsX20) 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. The variant was absent in 230146 control chromosomes (gnomAD). c.932delA has been reported in the literature in an individual affected with colon polyps (Susswein_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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