Submissions for variant NM_000251.3(MSH2):c.1387-4G>C

gnomAD frequency: 0.00011  dbSNP: rs376796243

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162829	SCV000213315	likely benign	Hereditary cancer-predisposing syndrome	2019-11-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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	RCV001086424	SCV000559190	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-05	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590179	SCV000601432	benign	not provided	2022-12-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590179	SCV000696212	uncertain significance	not provided	2016-10-28	criteria provided, single submitter	clinical testing	Variant summary: The MSH2 c.1387-4G>C variant involves the alteration of a non-conserved intronic nucleotide with 4/5 splice prediction tools predict no significant impact on normal splicing and ESE finder predicts alterations to ESE binding, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 5/120968 (1/24195), predominantly in the African cohort, 5/10274 (1/2054), which does not exceed the estimated maximal expected allele frequency for a pathogenic MSH2 variant of 1/1759. The variant of interest, to our knowledge, has not been reported in affected individuals via publications, although a clinical diagnostic laboratory has cited the variant as "uncertain significance." Therefore, until additional information becomes available, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Color Diagnostics, LLC DBA Color Health	RCV000162829	SCV000903781	likely benign	Hereditary cancer-predisposing syndrome	2015-10-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000590179	SCV001939592	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162829	SCV002528843	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-01	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003895090	SCV004714184	likely benign	MSH2-related condition	2022-03-11	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).