ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2458+4T>C (rs1038735071)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001712259 SCV000527911 likely benign not provided 2019-09-12 criteria provided, single submitter clinical testing
Ambry Genetics RCV000574853 SCV000669797 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-17 criteria provided, single submitter clinical testing The c.2458+4T>C intronic variant results from a T to C substitution 4 nucleotides after coding exon 14 in the MSH2 gene. This nucleotide position is poorly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing; however, direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000630059 SCV000751015 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-11-10 criteria provided, single submitter clinical testing
Color Health, Inc RCV000574853 SCV001357312 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000431124 SCV001442772 uncertain significance not specified 2020-10-30 criteria provided, single submitter clinical testing Variant summary: MSH2 c.2458+4T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251202 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2458+4T>C in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (3x) or likely benign (1x). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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