Submissions for variant NM_000251.3(MSH2):c.2635-3C>G

dbSNP: rs587779153

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001882768	SCV002264010	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-10-03	criteria provided, single submitter	clinical testing	This sequence change falls in intron 15 of the MSH2 gene. It does not directly change the encoded amino acid sequence of the MSH2 protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 27064304; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1275849). 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 16 and introduces a new termination codon (internal data). However the mRNA is not expected to undergo nonsense-mediated decay. This variant disrupts the MSH6 and MSH3 interaction domains of the MSH2 protein, as well as the helix-turn-helix domain, which are important for proper dimerization and normal protein functioning (PMID: 9774676, 18822302, 17531815). While functional studies have not been performed to directly test the effect of this variant on MSH2 protein function, this suggests that disruption of this region of the protein is causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV002440836	SCV002744752	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-10-20	criteria provided, single submitter	clinical testing	The c.2635-3C>G intronic variant results from a C to G substitution 3 nucleotides upstream from coding exon 16 in the MSH2 gene. This nucleotide position is well conserved in available vertebrate species. This variant has been identified in a proband who met Amsterdam I criteria for Lynch syndrome and tumor demonstrated high microsatellite instability with loss of MSH2/MSH6 expression by immunohistochemistry (Borras E et al. Cancer Prev Res (Phila), 2017 Oct;10:580-587). This variant has been identified in multiple probands whose Lynch syndrome-associated tumor demonstrated high microsatellite instability and loss of MSH2/MSH6 or MSH2 expression by immunohistochemistry (Sjursen W et al. Mol Genet Genomic Med, 2016 Mar;4:223-31; external laboratory communication). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV001694187	SCV001906355	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001694187	SCV001969371	uncertain significance	not provided		no assertion criteria provided	clinical testing