Submissions for variant NM_000179.3(MSH6):c.354A>G (p.Thr118=)

gnomAD frequency: 0.00002  dbSNP: rs558590898

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001089387	SCV000253109	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-11-30	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455691	SCV000539700	likely benign	not specified	2016-10-26	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Silent variant. MaxMAF = 0.012% in ExAC. Classified in ClinVar as Likely Benign by Invitae (1 star).
Ambry Genetics	RCV000575136	SCV000662436	likely benign	Hereditary cancer-predisposing syndrome	2016-06-29	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	RCV000575136	SCV000690364	likely benign	Hereditary cancer-predisposing syndrome	2016-04-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756350	SCV000884136	likely benign	not provided	2017-06-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000756350	SCV000888278	likely benign	not provided	2018-04-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000756350	SCV001943381	likely benign	not provided	2018-07-09	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798667	SCV002042053	likely benign	Breast and/or ovarian cancer	2020-01-03	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000455691	SCV005090470	likely benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355723	SCV001550681	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Thr118= variant was not identified in the literature nor was it identified in the COGR, Cosmic, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors databases. The variant was identified in dbSNP (ID: rs558590898) as “With Likely benign allele”, ClinVar (as likely benign by Invitae, Partners HealthCare Personalized Medicine, Ambry Genetics, and Color), and Clinvitae (3x). The variant was identified in control databases in 4 of 246272 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 15304 chromosomes (freq: 0.00007), European (Non-Finnish) in 2 of 111720 chromosomes (freq: 0.00002), and East Asian in 1 of 17248 chromosomes (freq: 0.000058); it was not observed in the Other, Latino, Ashkenazi Jewish, Finnish, and South Asian populations. The p.Thr118= 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.