Submissions for variant NM_000179.3(MSH6):c.2271C>T (p.Thr757=)

gnomAD frequency: 0.00004  dbSNP: rs142172006

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162764	SCV000213241	likely benign	Hereditary cancer-predisposing syndrome	2014-12-08	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	RCV001088780	SCV000260261	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000589413	SCV000513690	likely benign	not provided	2019-02-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162764	SCV000685273	likely benign	Hereditary cancer-predisposing syndrome	2016-07-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000421153	SCV000695805	likely benign	not specified	2019-08-29	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000589413	SCV000805860	likely benign	not provided	2017-12-27	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000421153	SCV002760661	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995216	SCV004841938	likely benign	Lynch syndrome	2023-11-30	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357571	SCV001553077	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Thr757= variant was not identified in the literature nor was it identified in the UMD-LSDB database. The variant was identified in dbSNP (rs142172006) as “with likely benign, uncertain significance allele” and ClinVar (classified as likely benign by Invitae, Ambry Genetics, Color and 2 other submitters; and as uncertain significance by Integrated Genetics). The variant was identified in control databases in 7 of 276,782 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 24,022 chromosomes (freq: 0.00004) and European in 6 of 126,318 chromosomes (freq: 0.00005); it was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish or South Asian populations. In our laboratory, the variant was identified as co-occurring with a pathogenic MSH6 variant (c.1883G>A, p.Trp628*). The p.Thr757= 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. The variant occurs at a non-highly conserved nucleotide outside of the splicing consensus sequence and 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.