ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1046C>T (p.Pro349Leu) (rs587779067)

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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) RCV000076009 SCV000107020 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability >0.99
Ambry Genetics RCV000217955 SCV000278096 pathogenic Hereditary cancer-predisposing syndrome 2019-06-06 criteria provided, single submitter clinical testing In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s);Rarity in general population databases (dbsnp, esp, 1000 genomes);Structural Evidence;Good segregation with disease (lod 1.5-3 = 5-9 meioses)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508278 SCV000601423 likely pathogenic not provided 2017-03-08 criteria provided, single submitter clinical testing
Invitae RCV000694503 SCV000822952 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-02-11 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 349 of the MSH2 protein (p.Pro349Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with Lynch syndrome in a family (PMID: 21926548). It also has been reported in individuals and families affected with Lynch syndrome (PMID: 25420488, 25117503, 15342696). ClinVar contains an entry for this variant (Variation ID: 90514). Experimental studies have shown that this missense change results in reduced MSH2 protein levels and high microsatellite slippage (PMID: 26951660). A different missense substitution at this codon (p.Pro349Arg) has been determined to be pathogenic (PMID: 21239990, 27606285, 24278394, 26951660). This suggests that the proline residue is critical for MSH2 protein function and that other missense substitutions at this position may also be pathogenic. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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