Submissions for variant NM_000251.3(MSH2):c.2634+5G>A

dbSNP: rs267608017

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001525586	SCV001735750	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-05-21	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution in the conserved guanine at the +5 position of intron 15 of the MSH2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing (PMID: 35449021). Two other single nucleotide substitutions with similar predicted splicing impact, c.2634+5G>C and c.2634+5G>T, have been shown to cause exon 15 skipping in patient RNA samples (PMID: 11074494, 18033691) and in a minigene splicing assay (PMID: 18561205), respectively. To our knowledge, this variant has not been reported in functional studies nor in individuals affected with hereditary cancer in the literature. This variant has been detected in individuals affected with MSH2-associated and/or MSH2-deficient cancer (Color internal data, Communication with external laboratories). The two other variants at this position, c.2634+5G>C and c.2634+5G>T, have been reported in multiple Lynch syndrome families with DNA mismatch repair-deficient colorectal cancer (PMID: 11074494, 15713769, 16807412, 18561205, 31101557). In one family, the c.2634+5G>C variant segregated in 5 affected family members (PMID: 18033691). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Ambry Genetics	RCV001525586	SCV005141914	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-29	criteria provided, single submitter	clinical testing	The c.2634+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 15 in the MSH2 gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive; however, direct evidence is insufficient at this time (Ambry internal data). Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005094698	SCV005754473	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-07-02	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. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of MSH2-related conditions (PMID: 35430768). ClinVar contains an entry for this variant (Variation ID: 1172006). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with inconclusive levels of altered splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005237874	SCV005886754	likely pathogenic	Hereditary nonpolyposis colon cancer	2025-02-25	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.2634+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. One predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251350 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2634+5G>A has been reported in the literature in at least one individual affected with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 35430768). ClinVar contains an entry for this variant (Variation ID: 1172006). In addition, other variants affecting this nucleotide (c.2634+5G>T, c.2634+5G>C) have been reported to associate with Hereditary Nonpolyposis Colorectal Cancer. Based on the evidence outlined above, the variant was classified as likely pathogenic.