Submissions for variant NM_000251.3(MSH2):c.645+3A>G

gnomAD frequency: 0.00001  dbSNP: rs587779168

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000419965	SCV000530721	likely benign	not specified	2016-08-04	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.
Invitae	RCV000627695	SCV000548191	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000491694	SCV000580438	likely benign	Hereditary cancer-predisposing syndrome	2018-01-20	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000419965	SCV000731402	uncertain significance	not specified	2017-03-06	criteria provided, single submitter	clinical testing	The c.645+3A>G variant in MSH2 has not been previously reported in individuals w ith Lynch syndrome but has been identified in 1/8640 of East Asian chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs587779168). This variant is located in the 5' splice region. Computational too ls do not suggest an impact to splicing. However, this information is not predic tive enough to rule out pathogenicity. In addition, this variant was classified as a variant of uncertain significance on Sept. 5, 2013 by the ClinGen-approved InSiGHT expert panel (SCV000107696.2). In summary, the clinical significance of the c.645+3A>G variant is uncertain.
Color Diagnostics, LLC DBA Color Health	RCV000491694	SCV000908279	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-24	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the +3 position of intron 3 of the MSH2 gene. An RNA study performed demonstrated this variant had no impact on RNA splicing (PMID: 31642931). This variant has been reported in an individual affected with an unspecified cancer (PMID: 31386297). This variant has been identified in 3/250270 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	RCV000419965	SCV001774497	likely benign	not specified	2021-07-11	criteria provided, single submitter	clinical testing	Variant summary: MSH2 c.645+3A>G alters a 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. This has been further corroborated by RNA studies demonstrating no abnormal splicing leading to its re-classification as a likely benign variant (Karam_2019). The variant allele was found at a frequency of 1.2e-05 in 250270 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.645+3A>G has been reported in the literature among individuals undergoing multigene panel testing for hereditary cancer (example, Kiyozumi_2019, Karam_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=3, VUS, n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477472	SCV004221012	likely benign	not provided	2023-06-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997178	SCV004821993	uncertain significance	Lynch syndrome	2023-08-15	criteria provided, single submitter	clinical testing