Submissions for variant NM_000251.3(MSH2):c.2458+4T>C

gnomAD frequency: 0.00001  dbSNP: rs1038735071

Total submissions: 6

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	likely benign	Hereditary cancer-predisposing syndrome	2020-12-10	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000630059	SCV000751015	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000574853	SCV001357312	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-06	criteria provided, single submitter	clinical testing	This variant causes a T to C nucleotide substitution at the +4 position of intron 14 of the MSH2 gene. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 1/251202 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
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.
All of Us Research Program, National Institutes of Health	RCV004000450	SCV004825405	uncertain significance	Lynch syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This variant causes a T to C nucleotide substitution at the +4 position of intron 14 of the MSH2 gene. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 1/251202 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.