Submissions for variant NM_000179.3(MSH6):c.2526T>G (p.Ala842=)

gnomAD frequency: 0.00001  dbSNP: rs772394197

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165962	SCV000216719	likely benign	Hereditary cancer-predisposing syndrome	2014-10-07	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	RCV000232449	SCV000283755	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000427523	SCV000529903	likely benign	not specified	2016-07-14	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	RCV000165962	SCV000685292	likely benign	Hereditary cancer-predisposing syndrome	2016-10-24	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995467	SCV004842560	likely benign	Lynch syndrome	2023-12-18	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354593	SCV001549243	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Ala842= variant was not identified in the literature nor was it identified in the COGR, Cosmic, MutDB, UMD-LSDB, Zhejiang Colon Cancer Database, and Mismatch Repair Genes Variant databases. The variant was identified in dbSNP (ID: rs772394197) as with likely benign allele; in the ClinVar and Clinvitae databases as likely benign by Ambry Genetics, Invitae, GeneDx and Color Genomics; in the Insight Colon Cancer Gene Variant Database and the Insight Hereditary Tumors 1X with no probable effect on function. The variant was not identified 1000 Genomes or in the NHLBI GO Exome Sequencing projects. The variant was identified in control databases in 8 of 244390 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). It was observed in the East Asian population in 8 of 17198 chromosomes (freq: 0.0005), but not in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, Finnish, and South Asian populations. The p.Ala842= 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.