Submissions for variant NM_000251.3(MSH2):c.929T>G (p.Leu310Arg)

dbSNP: rs63750640

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000524912	SCV000625480	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-10-20	criteria provided, single submitter	clinical testing	Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 333574060) indicates that this missense variant is expected to disrupt MSH2 function. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 91246). This missense change has been observed in individual(s) with Lynch syndrome associated cancers (PMID: 30374176). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 310 of the MSH2 protein (p.Leu310Arg).
Ambry Genetics	RCV000567639	SCV000673888	pathogenic	Hereditary cancer-predisposing syndrome	2021-02-25	criteria provided, single submitter	clinical testing	The p.L310R pathogenic mutation (also known as c.929T>G), located in coding exon 5 of the MSH2 gene, results from a T to G substitution at nucleotide position 929. The leucine at codon 310 is replaced by arginine, an amino acid with dissimilar properties. This mutation was found to segregate with disease in one family meeting Amsterdam criteria, including two affected carriers whose tumors demonstrated loss of MSH2 and MSH6 protein expression by immunohistochemistry analysis (IHC) (Tsai GJ et al. Genet Med, 2019 06;21:1435-1442). This alteration has been reported in two additional individuals diagnosed with MSI-H colon cancer with absent MSH2 staining on IHC, one of whom was diagnosed at age 45 or younger (Perea J et al. Ann. Surg. Oncol., 2011 Nov;18:3285-91; Latham A et al. J Clin Oncol, 2019 02;37:286-295). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was determined to be functionally deleterious (Jia X et al. Am J Hum Genet, 2021 01;108:163-175). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
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 analyze.myvariant.org (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.