Submissions for variant NM_000179.3(MSH6):c.2391C>T (p.Asp797=)

gnomAD frequency: 0.00001  dbSNP: rs754870044

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000228212	SCV000283748	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000418244	SCV000522065	likely benign	not specified	2017-11-27	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.
Ambry Genetics	RCV000490895	SCV000580253	likely benign	Hereditary cancer-predisposing syndrome	2015-04-24	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.
Color Diagnostics, LLC DBA Color Health	RCV000490895	SCV000685284	likely benign	Hereditary cancer-predisposing syndrome	2017-01-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000418244	SCV001339015	likely benign	not specified	2024-03-04	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000490895	SCV002535731	likely benign	Hereditary cancer-predisposing syndrome	2021-11-27	criteria provided, single submitter	curation
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357654	SCV001553182	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Asp797= variant was not identified in the literature nor was it identified in the COGR, Cosmic, UMD-LSDB, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database, databases. The variant was identified in dbSNP (ID: rs754870044) as With Likely benign allele, ClinVar (classified as likely benign by Invitae, GeneDx, Ambry Genetics, Color Genomics) and Clinvitae. The variant was identified in control databases in 3 of 245566 chromosomes at a frequency of 0.000012 (Genome Aggregation Database Feb 27, 2017). It was observed in the East Asian population in 3 of 17248 chromosomes (freq: 0.0002); but not in the African, Other, Latino, European, Ashkenazi Jewish, Finnish, and South Asian populations. The p.Asp797= 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.