Submissions for variant NM_000251.3(MSH2):c.1014A>C (p.Gly338=)

gnomAD frequency: 0.00002  dbSNP: rs774083607

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163386	SCV000213926	likely benign	Hereditary cancer-predisposing syndrome	2015-07-13	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	RCV000195788	SCV000253149	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163386	SCV000684893	likely benign	Hereditary cancer-predisposing syndrome	2017-05-22	criteria provided, single submitter	clinical testing
GeneDx	RCV001697120	SCV000723457	likely benign	not provided	2019-03-11	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23047549)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000605224	SCV001362026	likely benign	not specified	2019-07-09	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163386	SCV002528799	likely benign	Hereditary cancer-predisposing syndrome	2020-11-05	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001697120	SCV004220931	likely benign	not provided	2022-04-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995253	SCV004824543	likely benign	Lynch syndrome	2023-11-30	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355749	SCV001550715	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH2 p.Gly338= variant was identified in 1 of 3786 proband chromosomes (frequency: 0.00026) from individuals or families with ovarian cancer (Pal 2012). The variant was also identified in dbSNP (ID: rs774083607) as With Likely benign allele, ClinVar (classified as likely benign by Ambry Genetics, Invitae), Clinvitae (classified as likely benign by ClinVar and Invitae), databases. The variant was not identified in UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database, databases. The variant was identified in control databases in 5 of 246226 chromosomes at a frequency of 0.00002 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Gly338Gly 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, HumanSpliceFinder) 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. This variant is classified as a variant of uncertain significance.