Submissions for variant NM_000251.3(MSH2):c.2087C>T (p.Pro696Leu)

dbSNP: rs267607994

Total submissions: 6

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV001034643	SCV000260475	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-10-22	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 696 of the MSH2 protein (p.Pro696Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Lynch syndrome (PMID: 12624141, 19419416, 23729658, 26053027). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 90881). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is expected to disrupt MSH2 function. Experimental studies have shown that this missense change affects MSH2 function (PMID: 26951660, 27629256, 29731845). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000492029	SCV000580387	pathogenic	Hereditary cancer-predisposing syndrome	2021-03-09	criteria provided, single submitter	clinical testing	The p.P696L pathogenic mutation (also known as c.2087C>T), located in coding exon 13 of the MSH2 gene, results from a C to T substitution at nucleotide position 2087. The proline at codon 696 is replaced by leucine, an amino acid with similar properties. This mutation was reported in a Taiwanese individual whose family history met Amsterdam II criteria for Lynch syndrome and tumor displayed loss of MSH2 protein expression by immunohistochemistry as well as high microsatellite instability (MSI-H) (Tang R et al. Clin. Genet., 2009 Apr;75:334-45; Kamiza AB et al. PLoS One, 2015 Jun;10:e0130018). This variant was also reported to segregate in two affected individuals of a French family (Parc Y et al. J. Med. Genet., 2003 Mar;40:208-13) and has been identified in individuals either meeting Amsterdam criteria or whose tumors demonstrate absent staining of MSH2 and MSH6 by IHC (Ambry internal data). In two different functional studies, this alteration showed reduced MSH2 protein expression and deficient mismatch repair activity compared to wild type (Houlleberghs H et al. Proc. Natl. Acad. Sci. U.S.A., 2016 Apr;113:4128-33; Tricarico R et al. Hum. Mutat. 2017 Jan;38:64-77) and also demonstrated reduced MSH2 and MSH6 protein interaction in a yeast two-hybrid assay (Zhang X et al. Oncol Lett. 2018 May;15(5):6275-82) In an in vitro complementation assay, this variant was determined to be functionally deficient (Drost M et al. Genet Med, 2019 07;21:1486-1496). 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.
Myriad Genetics, Inc.	RCV003452886	SCV004186721	likely pathogenic	Lynch syndrome 1	2023-08-07	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 27629256, 26951660]. This variant is expected to disrupt protein structure [Myriad internal data].
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000501546	SCV005199183	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000501546	SCV000592534	uncertain significance	not provided		no assertion criteria provided	clinical testing	The p.Pro696Leu variant has been reported in 2 of 350 proband chromosomes meeting either the Amsterdam criteria for HNPCC or had a suggestive family history associated with a MSI phenotype in the tumor. None of the 600 control chromosomes tested had the variant (Tang_2009_19419416;Tournier_2008_18561205). The variant has also been reported in the UMD (x2) and LOVD (x8) databases. The p.Pro696 residue is conserved across mammals and computational analyses (PolyPhen, SIFT, AlignGVGD) suggest that the p.Pro696Leu variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. In one study, the tumor harboring the variant was associated with a loss of MSH2 protein expression & high level of MSI in tumors (Tang_2009_19419416). However, in another study, functional analysis using ex vivo splicing assay demonstrated that this variant had no effect (Tournier_2008_18561205). In summary, based on the above information, the clinical significance of this variant cannot be determined at this time. This variant is classified as a variant of unknown significance.