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

Total submissions: 5

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.