ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.839dup (p.Leu280fs)

dbSNP: rs63750091
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076733 SCV000107770 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Baylor Genetics RCV003460717 SCV004196861 pathogenic Lynch syndrome 1 2023-03-23 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV003584549 SCV004356638 pathogenic Hereditary cancer-predisposing syndrome 2021-12-16 criteria provided, single submitter clinical testing This variant inserts 1 nucleotide in exon 5 of the MSH2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with or suspected of having Lynch syndrome (PMID: (7881432, 10530344, 10732761, 14970868, 21642682, 29967336)). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Ambry Genetics RCV003584549 SCV005033751 pathogenic Hereditary cancer-predisposing syndrome 2023-10-16 criteria provided, single submitter clinical testing The c.839dupT pathogenic mutation, located in coding exon 5 of the MSH2 gene, results from a duplication of T at nucleotide position 839, causing a translational frameshift with a predicted alternate stop codon (p.L280Ffs*4). This alteration has been reported in one family meeting Amsterdam criteria for Lynch syndrome and another family with clinical suspicion of Lynch syndrome (Lazar V et al. Hum Mol Genet, 1994 Dec;3:2257-60; Ponz de Leon M et al. Br J Cancer, 2004 Feb;90:882-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.

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