Submissions for variant NM_000179.3(MSH6):c.3300G>C (p.Thr1100=)

dbSNP: rs540252208

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163963	SCV000214562	likely benign	Hereditary cancer-predisposing syndrome	2015-05-13	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.
GeneDx	RCV001697091	SCV000527839	likely benign	not provided	2019-05-08	criteria provided, single submitter	clinical testing
Invitae	RCV000466003	SCV000561522	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163963	SCV000911939	likely benign	Hereditary cancer-predisposing syndrome	2018-04-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163963	SCV002528008	likely benign	Hereditary cancer-predisposing syndrome	2022-03-15	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV003995302	SCV004835043	likely benign	Lynch syndrome	2023-11-30	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357868	SCV001553459	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Thr1100Thr variant was not identified in the literature nor was it identified in the Genesight-COGR, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs540252208) as “With Likely benign allele”, ClinVar (3x, as likely benign, by Ambry, GeneDx, Invitae), Clinvitae (3x, as likely benign and 1x as benign by clinvar), Cosmic (2x large intestine adenocarcinoma, 2 x endometrium carcinoma), databases. The variant was identified in control databases in 13 of 121374 chromosomes (freq. 0.0002) in the following populations: South Asian in 11 of 16512 chromosomes (freq. 0.00066), Latino in 1 of 11552 chromosomes (freq. 0.000086), European in 1 of 66732 chromosomes (freq. 0.000015), but was not seen in African, East Asian, Finnish and other populations in the Exome Aggregation Consortium database (August 8th 2016) and in 1 of 246224 chromosomes at a frequency of 0.000004 in European population, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Thr1100 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.