Submissions for variant NM_000179.3(MSH6):c.2904C>G (p.Val968=)

gnomAD frequency: 0.00004  dbSNP: rs150683226

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163540	SCV000214098	likely benign	Hereditary cancer-predisposing syndrome	2015-06-03	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.
Invitae	RCV001086343	SCV000283771	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
Counsyl	RCV000411849	SCV000488555	likely benign	Lynch syndrome 5	2016-05-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000440970	SCV000513695	benign	not specified	2015-07-13	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Color Diagnostics, LLC DBA Color Health	RCV000163540	SCV000685330	likely benign	Hereditary cancer-predisposing syndrome	2017-02-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759854	SCV000889476	likely benign	not provided	2018-05-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000440970	SCV000917789	benign	not specified	2018-12-20	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.2904C>G alters a non-conserved nucleotide resulting in a synonymous change. 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 0.00012 in 239046 control chromosomes, predominantly at a frequency of 0.00026 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2-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 a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.2904C>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000440970	SCV002552316	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000759854	SCV002822649	likely benign	not provided	2022-10-01	criteria provided, single submitter	clinical testing	MSH6: BP4, BP7
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150002	SCV003838320	likely benign	Breast and/or ovarian cancer	2022-05-17	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000411849	SCV004015983	benign	Lynch syndrome 5	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000411849	SCV004018894	benign	Lynch syndrome 5	2023-03-28	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
Mayo Clinic Laboratories, Mayo Clinic	RCV000440970	SCV000691935	likely benign	not specified		no assertion criteria provided	clinical testing