ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1510+2T>C (rs1060502023)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000461276 SCV000548282 likely pathogenic Lynch syndrome 2016-04-30 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 9 of the MSH2 gene. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MSH2-related disease. In summary, donor and acceptor splice site variants are typically truncating (PMID: 16199547), and truncating variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). However, without additional functional and/or genetic data, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000491134 SCV000580520 pathogenic Hereditary cancer-predisposing syndrome 2020-09-11 criteria provided, single submitter clinical testing The c.1510+2T>C intronic pathogenic mutation results from a T to C substitution two nucleotides after coding exon 9 in the MSH2 gene. In one study, this alteration was identified in 1/1231 colorectal cancer cases and was not present in the control group (DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569). This alteration has also been identified in a proband whose colorectal tumor demonstrated loss of MSH2 and MSH6 staining on immunohistochemistry (Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic/a disease-causing mutation.
Johns Hopkins Genomics, Johns Hopkins University RCV001543671 SCV001762358 pathogenic Lynch syndrome I 2021-07-16 criteria provided, single submitter clinical testing This MSH2 variant is absent in a large population dataset and has been reported in ClinVar. This variant destroys the native donor (5') splice site for exon 9 and is predicted to cause aberrant mRNA splicing. It has been reported in an individual with colorectal cancer (CRC) who underwent targeted germline DNA sequencing. We consider c.1510+2T>C to be pathogenic.

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