Submissions for variant NM_000179.3(MSH6):c.3294C>T (p.Cys1098=)

gnomAD frequency: 0.00001  dbSNP: rs766341781

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000571862	SCV000673929	likely benign	Hereditary cancer-predisposing syndrome	2015-11-02	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.
GeneDx	RCV000827315	SCV000968953	likely benign	not provided	2018-05-14	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	RCV000571862	SCV001348352	likely benign	Hereditary cancer-predisposing syndrome	2018-11-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000504143	SCV001362728	likely benign	not specified	2020-01-31	criteria provided, single submitter	clinical testing
Invitae	RCV001434443	SCV001637249	likely benign	Hereditary nonpolyposis colorectal neoplasms	2021-06-23	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004003520	SCV004835039	likely benign	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000827315	SCV000592633	likely benign	not provided		no assertion criteria provided	clinical testing	The p.Cys1098Cys variant was not identified in the literature nor was it identified in the Clinvitae database, COSMIC, InSiGHT Colon Cancer Gene Variant Database (LOVD), Zhejiang Colon Cancer Database (LOVD), ClinVar database, GeneInsight - COGR database and UMD. The variant was identified in the dbSNP database (ID#: rs766341781) but no frequency information was provided, thus the prevalence of this variant in the general population could not be determined; and in the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 4 of 16512 alleles (frequency: 0.0002) in the South Asian population, although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. It was not observed in European (Non-Finnish)/East Asian/Other/African/Latino/European (Finnish) individuals from the ExAC dataset. The p.Cys1098Cys 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 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in the creation of a 3’ cryptic splice site; however, this is not very predictive of pathogenicity. 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.