Submissions for variant NM_000179.3(MSH6):c.4002-10del

dbSNP: rs59056100

Total submissions: 13

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%
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000610486	SCV000744304	benign	Lynch syndrome 5	2015-09-21	criteria provided, single submitter	clinical testing
GeneDx	RCV001668179	SCV001882423	benign	not provided	2019-08-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000500093	SCV002568060	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149726	SCV003838332	benign	Breast and/or ovarian cancer	2021-12-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001668179	SCV004222028	benign	not provided	2023-07-05	criteria provided, single submitter	clinical testing
Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	RCV000500093	SCV004233307	benign	not specified	2024-01-24	criteria provided, single submitter	clinical testing	This variant is classified as Benign based on local population frequency. This variant was detected in 55% of patients studied by a panel of primary immunodeficiencies. Number of patients: 52. Only high quality variants are reported.
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 (http://opengenetics.ca/) 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	Lynch syndrome 5		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000500093	SCV001906272	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000500093	SCV001978331	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001668179	SCV002036887	likely benign	not provided		no assertion criteria provided	clinical testing