ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.929T>G (p.Leu310Arg) (rs63750640)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000524912 SCV000625480 uncertain significance Hereditary nonpolyposis colon cancer 2017-06-28 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 310 of the MSH2 protein (p.Leu310Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected colorectal cancer (PMID: 21590452). ClinVar contains an entry for this variant (Variation ID: 91246). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In addition, an algorithm developed specifically for the MSH2 gene (PMID: 22290698), suggests that this missense change is likely to be deleterious. However, these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on MSH2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000567639 SCV000673888 uncertain significance Hereditary cancer-predisposing syndrome 2016-10-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
University of Washington Department of Laboratory Medicine, University of Washington RCV000076751 SCV000886440 pathogenic Lynch syndrome 2018-04-03 criteria provided, single submitter research The MSH2 variant designated as NM_000251.2:c.929T>G (p.L310R) is classified as pathogenic. Cosegregation analysis of one observed family was performed using (Rañola et al, 2018, PMID:28965303). This allele had a likelihood ratio of 19.6 to 1 (Thompson, et al., 2003, PMID:2900794) indicating that this allele is likely to explain the Lynch syndrome associated cancers in this family (e.g. colon cancer, gastric cancer, ovarian cancer, endometrial cancer, and sebaceous adenoma). The genomic position is highly conserved. The variant is predicted to be probably damaging by analysis with computerized tools PolyPhen 2 and SIFT and has a MAPP score of 33.02. By consensus, prior probability of pathogenicity based on in-silico scores are capped at a maximum of 90%. In Bayesian analysis, the likelihood ratio from our study, 19.6 to 1, was combined with the 90% prior probability to give a 99% probability of pathogenicity, which is consistent with a classification of pathogenic. This finding is also consistent with other supporting data. This variant was identified in two family members whose colon tumors had loss of MSH2 and MSH6. It has also been reported by the InSIGHT consortium database in one patient whose tumor had loss of MSH2 and MSH6. A different variant at the same amino acid position is known to be deleterious (Chao 2008, PMID:18383312). An algorithm developed specifically for the MSH2 gene suggests that this missense change is likely to be deleterious (Ali et al, 2012, PMID:22290698). The variant is not listed in population databases such as ExAC or gnomAD. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives >99% probability of pathogenicity, which is consistent with a classification of pathogenic. This variant is expected to alter MSH2 function and modify cancer risk for Lynch syndrome. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.

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