ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2087C>T (p.Pro696Leu) (rs267607994)

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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) RCV000076383 SCV000107410 pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability >0.99
Invitae RCV000076383 SCV000260475 uncertain significance Lynch syndrome 2015-09-04 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 696 of the MSH2 protein (p.Pro696Leu). 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 and has been reported in patients and families affected with colon cancer with weak evidence of disease co-segregation (PMID: 12624141, 19419416). ClinVar contains entry for this variant (Variation ID: 90881). General algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) and multifactorial likelihood analysis (PMID: 24362816) all suggest that this missense change is likely to be deleterious, although these predictions have not been confirmed by published functional studies. In summary, this is a rare missense variant with protein effect prediction and multifactorial likelihood analysis suggesting that it may be deleterious, but evidence for disease co-segregation remains weak. For these reasons, this change has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000492029 SCV000580387 likely pathogenic Hereditary cancer-predisposing syndrome 2018-09-06 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)
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000501546 SCV000592534 uncertain significance not specified 2014-06-12 criteria provided, single submitter clinical testing

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