Submissions for variant NM_000179.3(MSH6):c.3557-4dup

dbSNP: rs267608102

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074886	SCV000108099	no known pathogenicity	Lynch syndrome	2013-09-05	reviewed by expert panel	research	MAF >1%
Ambry Genetics	RCV000162507	SCV000212898	likely benign	Hereditary cancer-predisposing syndrome	2012-11-06	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Color Diagnostics, LLC DBA Color Health	RCV000162507	SCV000690369	benign	Hereditary cancer-predisposing syndrome	2022-01-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000584641	SCV001360589	benign	not specified	2019-02-07	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3557-4dupT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.15 in 27938 control chromosomes in the gnomAD database, including 314 homozygotes. The observed variant frequency is approximately 1075 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), strongly suggesting that the variant is benign. c.3557-4dupT has been reported in the literature in multiple affected individuals and also, a large number of controls and has been described as a polymorphism (Wasielewski_2010, Vahteristo_2005, Charames_2000). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV001689613	SCV001910578	benign	not provided	2019-11-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162507	SCV002528044	benign	Hereditary cancer-predisposing syndrome	2022-01-06	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000584641	SCV002552349	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477212	SCV002798704	likely benign	Endometrial carcinoma; Lynch syndrome 5; Mismatch repair cancer syndrome 3	2022-05-13	criteria provided, single submitter	clinical testing
Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	RCV000584641	SCV004233763	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 25% of patients studied by a panel of primary immunodeficiencies. Number of patients: 24. Only high quality variants are reported.
Mayo Clinic Laboratories, Mayo Clinic	RCV000584641	SCV000691940	benign	not specified		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000613784	SCV000734221	benign	Lynch syndrome 5		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000584641	SCV001800145	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000584641	SCV001905989	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000584641	SCV001921387	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000584641	SCV001926798	benign	not specified		no assertion criteria provided	clinical testing