Submissions for variant NM_000251.3(MSH2):c.2595C>T (p.Ile865=)

gnomAD frequency: 0.00001  dbSNP: rs547695133

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216482	SCV000276842	likely benign	Hereditary cancer-predisposing syndrome	2015-08-27	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	RCV001084482	SCV000559230	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000216482	SCV000685063	likely benign	Hereditary cancer-predisposing syndrome	2017-02-12	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679308	SCV000806034	likely benign	not provided	2017-10-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000679308	SCV001850077	likely benign	not provided	2020-11-24	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000216482	SCV002534493	likely benign	Hereditary cancer-predisposing syndrome	2021-12-23	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV003997992	SCV004826542	likely benign	Lynch syndrome	2023-11-30	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000679308	SCV001548924	likely benign	not provided		no assertion criteria provided	clinical testing	The MSH2 p.Ile865= variant was not identified in the literature nor was it identified in the Genesight-COGR, Cosmic, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors Databases. The variant was identified in dbSNP (ID: rs547695133) as “with likely benign allele”, and in the ClinVar and Clinvitae databases as likely benign by Ambry Genetics and Invitae. Furthermore, the variant was identified in control databases in 29 of 246222 chromosomes at a frequency of 0.0001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include and South Asian in 29 of 30774 chromosomes (freq: 0.0009), while the variant was not observed in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, East Asian, European Finnish, populations. The p.Ile865= 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.