Submissions for variant NM_000251.3(MSH2):c.2634G>C (p.Glu878Asp)

dbSNP: rs63751624

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076524	SCV000107554	uncertain significance	Lynch syndrome	2018-06-13	reviewed by expert panel	curation	G>non-G at last base of exon with first 6 intronic bases not GTRRGT; Insufficient evidence
Invitae	RCV000697249	SCV000825849	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2019-06-04	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid with aspartic acid at codon 878 of the MSH2 protein (p.Glu878Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant also falls at the last nucleotide of exon 15 of the MSH2 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals suspected of having Lynch syndrome (PMID: 18566915, 11208710, 25648859). It has also been observed to segregate with Lynch syndrome-associated cancers in a family (Invitae). ClinVar contains an entry for this variant (Variation ID: 91022). Experimental studies have shown that this missense change results in reduced MSH2 protein levels and high microsatellite slippage (PMID: 26951660). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. A different variant affecting this nucleotide (c.2634G>A) has been determined to be pathogenic (PMID: 23523604, 21778331, 21791569). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000772325	SCV000905443	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-03-14	criteria provided, single submitter	clinical testing	This missense variant changes the last nucleotide of exon 15 of the MSH2 gene, replacing a glutamine with aspartate, and is predicted to impair RNA splicing. RNA studies with carrier individuals have shown that this variant cause skipping of exon 15, and is predicted to result in a frameshift and premature truncation (PMID: 23523604, 26951660). This variant has been reported in individuals affected with Lynch syndrome (PMID: 11208710, 23523604, 25648859). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Ambry Genetics	RCV000772325	SCV002741267	pathogenic	Hereditary cancer-predisposing syndrome	2019-03-01	criteria provided, single submitter	clinical testing	The c.2634G>C variant (also known as p.E878D), located in coding exon 15 of the MSH2 gene, results from a G to C substitution at nucleotide position 2634. The amino acid change results in glutamic acid to aspartic acid at codon 878, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 15, which makes it likely to have some effect on normal mRNA splicing. This alteration has been detected in multiple Lynch syndrome patients meeting Amsterdam or Bethesda criteria and the tumor of one of these patients demonstrated high microsatellite instability and absent MSH2 protein expression on immunohistochemistry (Terdiman JP et al. Gastroenterology. 2001 Jan;120(1):21-30; Nilbert M et al. Fam Cancer. 2009;8(1):75-83). In addition, a splicing assay performed on an alteration at the same nucleotide position (c.2634G>A) demonstrated aberrant splicing and a functional assay performed on another alteration at the same nucleotide position (c.2634G>T) demonstrated attenuated MMR capacity (Pérez-Cabornero L et al. J Mol Diagn, 2013 May;15:380-90; Houlleberghs H et al. Proc Natl Acad Sci U S A. 2016 Apr 12;113(15):4128-33). Based on the available evidence, c.2634G>C is classified as a pathogenic mutation.
Myriad Genetics, Inc.	RCV003452928	SCV004186638	likely pathogenic	Lynch syndrome 1	2023-08-09	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 23523604].
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001723650	SCV004243572	likely pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001723650	SCV001952231	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001723650	SCV001967283	likely pathogenic	not provided		no assertion criteria provided	clinical testing