Submissions for variant NM_000179.3(MSH6):c.3801+4T>C

gnomAD frequency: 0.00002  dbSNP: rs758830540

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000567341	SCV000669936	likely benign	Hereditary cancer-predisposing syndrome	2020-09-25	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	RCV000567341	SCV000690406	likely benign	Hereditary cancer-predisposing syndrome	2016-10-25	criteria provided, single submitter	clinical testing
Invitae	RCV000630256	SCV000751212	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781586	SCV000919750	uncertain significance	not specified	2018-06-22	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3801+4T>C 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 5.4e-05 in 276962 control chromosomes (gnomAD), exclusively found in the East Asian population at a frequency 5-fold higher than the maximal allele frequency expected for a pathogenic variant, suggesting the variant may be a benign polymorphism. To our knowledge, no occurrence of c.3801+4T>C in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (1 x likely benign, 2 x VUS). Based on the evidence outlined above, the variant was classified as VUS - possibly benign variant.
Sema4, Sema4	RCV000567341	SCV002528070	likely benign	Hereditary cancer-predisposing syndrome	2021-08-10	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003900264	SCV004712567	likely benign	MSH6-related condition	2022-12-27	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).