Submissions for variant NM_000179.3(MSH6):c.3399T>C (p.Thr1133=)

gnomAD frequency: 0.00005  dbSNP: rs61748084

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162415	SCV000212754	likely benign	Hereditary cancer-predisposing syndrome	2014-08-26	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.
Counsyl	RCV000409777	SCV000487809	likely benign	Lynch syndrome 5	2015-11-17	criteria provided, single submitter	clinical testing
Invitae	RCV000458051	SCV000561535	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162415	SCV000690349	likely benign	Hereditary cancer-predisposing syndrome	2016-04-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000610158	SCV000729047	benign	not specified	2015-05-21	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000610158	SCV000919734	likely benign	not specified	2019-08-02	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162415	SCV002528018	likely benign	Hereditary cancer-predisposing syndrome	2021-08-17	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000409777	SCV004018881	benign	Lynch syndrome 5	2023-03-28	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001357664	SCV004563598	likely benign	not provided	2023-11-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998542	SCV004835064	likely benign	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357664	SCV001553194	likely benign	not provided		no assertion criteria provided	clinical testing	The MSH6 p.Thr1133= variant was not identified in the literature nor was it identified in the UMD-LSDB database. The variant was identified in dbSNP (ID: rs61748084) as "With Likely benign allele", and in ClinVar (classified as benign by GeneDx; as likely benign by Invitae, Ambry Genetics, Counsyl and Color). The variant was identified in control databases in 9 of 277182 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24036 chromosomes (freq: 0.00004), Latino in 1 of 34408 chromosomes (freq: 0.00003), European in 7 of 126686 chromosomes (freq: 0.00006); it was not observed in the Other, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Thr1133= 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) 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.