Submissions for variant NM_000251.3(MSH2):c.2458+8C>G

gnomAD frequency: 0.00003  dbSNP: rs189025757

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000122985	SCV000166273	likely benign	Hereditary nonpolyposis colorectal neoplasms	2022-11-03	criteria provided, single submitter	clinical testing
Counsyl	RCV000411107	SCV000489490	likely benign	Lynch syndrome 1	2016-10-11	criteria provided, single submitter	clinical testing
GeneDx	RCV000202181	SCV000513665	likely benign	not specified	2017-07-20	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Color Diagnostics, LLC DBA Color Health	RCV000580893	SCV000685046	likely benign	Hereditary cancer-predisposing syndrome	2015-07-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000202181	SCV000919708	uncertain significance	not specified	2021-04-28	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.2458+8C>G 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. 3/4 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 6.4e-05 in 251096 control chromosomes, predominantly at a frequency of 0.00026 within the Latino subpopulation in the gnomAD database. 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+8C>G in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrence with another pathogenic variant has been reported (TP53 c.637C>T, p.Arg213X) in our internal database, providing supporting evidence for a benign role. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202181	SCV002047332	likely benign	not specified	2021-03-24	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000202181	SCV002067214	likely benign	not specified	2018-07-17	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000411107	SCV004018346	benign	Lynch syndrome 1	2023-03-21	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Mayo Clinic Laboratories, Mayo Clinic	RCV000202181	SCV000257177	uncertain significance	not specified		no assertion criteria provided	research