Submissions for variant NM_000179.3(MSH6):c.4002-8A>C

gnomAD frequency: 0.00001  dbSNP: rs778957100

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205656	SCV000260078	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000579624	SCV000685479	likely benign	Hereditary cancer-predisposing syndrome	2016-06-20	criteria provided, single submitter	clinical testing
GeneDx	RCV001711614	SCV001941872	benign	not provided	2015-07-21	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30093976)
Sema4, Sema4	RCV000579624	SCV002536311	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-06	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267938	SCV002552384	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001711614	SCV004222036	likely benign	not provided	2023-05-09	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997591	SCV004815789	likely benign	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354582	SCV001549230	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 c.4002-8A>C variant was not identified in the literature nor was it identified in the UMD-LSDB database. The variant was identified in dbSNP (ID: rs778957100) as "With Likely benign allele", ClinVar (classified as likely benign by Invitae and Color). The variant was identified in our laboratory with a co-occurring pathogenic MSH2 variant (c.2444delA, p.Tyr815PhefsX3), increasing the likelihood that the c.4002-8A>C variant does not have clinical significance. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.4002-8A>C variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. However, 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.