Submissions for variant NM_000251.3(MSH2):c.2634G>A (p.Glu878=)

dbSNP: rs63751624

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076523	SCV000107553	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Variant causes splicing aberration leading to truncated protein: full inactivation of variant allele
Invitae	RCV000791439	SCV000260754	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-11-20	criteria provided, single submitter	clinical testing	This sequence change affects codon 878 of the MSH2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MSH2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Lynch syndrome (PMID: 21778331, 23523604, 31647837; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 91021). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 15 and introduces a premature termination codon (PMID: 23523604). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000491856	SCV000580401	pathogenic	Hereditary cancer-predisposing syndrome	2023-08-28	criteria provided, single submitter	clinical testing	The c.2634G>A pathogenic mutation (also known as p.E878E), located in coding exon 15 of the MSH2 gene, results from a G to A substitution at nucleotide position 2634. This nucleotide substitution does not change the amino acid at codon 878. 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 identified in several individuals with Lynch syndrome-associated tumors demonstrating absent MSH2/MSH6 staining by IHC analysis and family histories meeting Amsterdam criteria (Ambry Internal Data). This mutation was reported in a Spanish woman with a MSI-H endometrial cancer that demonstrated absent MSH2 staining by IHC analysis; her family history met Amsterdam criteria. Authors subsequently used mRNA analysis to demonstrate that this alteration results in skipping of exon 15 (Pérez-Cabornero L et al. Cancer Prev Res (Phila), 2011 Oct;4:1546-55; Pérez-Cabornero L et al. J Mol Diagn, 2013 May;15:380-90). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000519129	SCV000617594	likely pathogenic	not provided	2017-08-01	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.2634G>A at the cDNA level. Although the variant is silent at the codinglevel, preserving a Glutamic Acid at codon 878, it is located at the last nucleotide of exon 15 and disrupts the naturalsplice donor site leading to abnormal splicing. RT-PCR studies have demonstrated that MSH2 c.2634G>A causescomplete skipping of exon 15 (Pérez-Cabornero 2013). This variant has been observed in a family meeting Amsterdamcriteria and was found to segregate with endometrial cancer in two family members. The proband's tumor displayedabsence of the MSH2 and MSH6 proteins and microsatellite instability (MSI-H) (Pérez-Cabornero 2011). MSH2c.2634G>A was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 GenomesConsortium 2015, Lek 2016). The nucleotide which is altered, a guanine (G) at base 2634, is conserved acrossspecies. Based on currently available evidence, we consider this variant to be likely pathogenic
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001255522	SCV001431962	pathogenic	Hereditary nonpolyposis colon cancer	2020-08-24	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.2634G>A (p.Glu878Glu) alters a conserved nucleotide located at the last nucleotide of exon 15 adjacent to a canonical splice donor site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing by skipping on exon 15 (Perez-Cabornero_2013). The variant was absent in 251400 control chromosomes. c.2634G>A has been reported in the literature in individuals affected with Lynch Syndrome (example Perez-Cabornero_2011 and Katsidzira_2019). These data indicate that the variant is likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=2)/likely pathogenic. An expert panel (InSight) has submitted clinical significance assessment for this variant as Pathogenic to ClinVar before 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV003452927	SCV004188056	pathogenic	Lynch syndrome 1	2023-08-09	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 23523604]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 23523604].