Submissions for variant NM_000251.3(MSH2):c.1131A>G (p.Gln377=)

gnomAD frequency: 0.00002  dbSNP: rs181852377

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164645	SCV000215309	likely benign	Hereditary cancer-predisposing syndrome	2014-05-27	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	RCV000205248	SCV000259807	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000442945	SCV000513657	benign	not specified	2015-07-14	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	RCV000164645	SCV000684907	likely benign	Hereditary cancer-predisposing syndrome	2016-12-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001815239	SCV002063854	likely benign	not provided	2022-03-01	criteria provided, single submitter	clinical testing	MSH2: BP4, BP7
Sema4, Sema4	RCV000164645	SCV002528813	likely benign	Hereditary cancer-predisposing syndrome	2022-01-06	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV003995356	SCV004827154	likely benign	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357506	SCV001552994	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH2 p.Gln377= variant was not identified in the literature. The variant was identified in dbSNP (ID: rs181852377) as “With Likely benign allele”, ClinVar (classified as benign by GeneDx and as likely benign by Ambry Genetics, Invitae and Color), and UMD-LSDB (1x classified UV). The variant was identified in control databases in 12 of 246238 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017), observed in the following populations: European Non-Finnish in 5 of 111690 chromosomes (freq: 0.00005), East Asian in 4 of 17248 chromosomes (freq: 0.0002), and South Asian in 3 of 30780 chromosomes (freq: 0.0001), while not observed in the African, Other, Latino, Ashkenazi Jewish, or European Finnish populations. The p.Gln377= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.