ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1865C>T (p.Pro622Leu) (rs28929483)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076307 SCV000107329 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Abrogated function, >2 MSI-H tumours, co-segregation with disease & MAF 0.00. Multifactorial likelihood analysis posterior probability >0.99
Ambry Genetics RCV000566777 SCV000669704 pathogenic Hereditary cancer-predisposing syndrome 2017-12-27 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s);Good segregation with disease (lod 1.5-3 = 5-9 meioses);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Invitae RCV000630204 SCV000751160 pathogenic Hereditary nonpolyposis colorectal neoplasms 2018-07-24 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 622 of the MSH2 protein (p.Pro622Leu). 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 observed to segregate with Lynch syndrome in families (PMID: 8261515, 16616355) and has also been found in several other individuals affected with this condition (PMID: 16116158, 25117503, 22283331). This variant is also known as 1933C>_x0001_T (P622L) in the literature. ClinVar contains an entry for this variant (Variation ID: 1753). Numerous experimental studies have shown that this missense change disrupts MSH2 stability, blocking its interaction with binding partners and suppressing mismatch repair activity (PMID: 17720936, 12124176, 18822302, 21309037, 22102614, 24362816). Additionally, this variant has been determined to have a high probability of being pathogenic based on multifactorial likelihood analyses that used genetic, functional and in silico data (PMID: 22949379, 19267393). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000076307 SCV000917690 pathogenic Lynch syndrome 2017-11-03 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.1865C>T (p.Pro622Leu) variant involves the alteration of a conserved nucleotide located in the DNA mismatch repair protein MutS, core domain (IPR007696) (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). A yeast functional study showed 4% MMR activity associated with this variant (Gammie_2007). This variant is absent in 246248 control chromosomes in gnomAD. This variant was reported in multiple patients with LS and it showed perfect segregation with disease in affected families (Arnold_2009, Leach_1993). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
OMIM RCV000001823 SCV000021979 pathogenic Lynch syndrome I 1993-12-17 no assertion criteria provided literature only

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