ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.4002-10del (rs59056100)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074976 SCV000108192 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research Intronic variant with no effect on splicing & MAF 0.01-1%
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000610486 SCV000744304 benign Hereditary nonpolyposis colorectal cancer type 5 2015-09-21 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000074976 SCV000592668 benign Lynch syndrome no assertion criteria provided clinical testing The MSH6 c.4002-10delT variant was not identified in the literature nor was it identified in HGMD, COSMIC, MutDB, “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, “Zhejiang Colon Cancer Database”, Gene Insight through the Canadian Open Genetics Repository ( and UMD databases. The variant was identified in dbSNP (ID: rs267608137) “With likely benign allele, in NHLBI Exome Sequencing Project (Exome Variant Server) in 6 of 8244 Europeans Americans (frequency: 0.0007), and the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 9 of 99520 chromosomes, or 5 individuals from a population of African individuals, 1 from European (Non-Finnish), 1 from Latino, and 2 from South Asian individuals; and none from European (Finnish), East Asian, or Other individuals, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The variant was identified in “InSiGHT Colon Cancer Database” (3X) and in the ClinVar database (classified as likely benign by InSight). The variant was also found to co-occur with a pathogenic MSH6 mutation (c.2348_2349delGT) in 1 individual with endometrial cancer identified from our laboratory increasing the likelihood the c.4002-10delT variant is benign. The c.4002-10delT 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, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, we lean towards a more benign role for this variant. This variant is classified as benign.
Mayo Clinic Laboratories, Mayo Clinic RCV000500093 SCV000691944 benign not specified no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000610486 SCV000734223 benign Hereditary nonpolyposis colorectal cancer type 5 no assertion criteria provided clinical testing

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