Submissions for variant NM_000179.3(MSH6):c.3246G>A (p.Pro1082=)

dbSNP: rs3136351

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163801	SCV000214384	likely benign	Hereditary cancer-predisposing syndrome	2014-12-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Eurofins Ntd Llc (ga)	RCV000724321	SCV000230868	uncertain significance	not provided	2014-10-30	criteria provided, single submitter	clinical testing
Invitae	RCV001085889	SCV000260070	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-26	criteria provided, single submitter	clinical testing
Counsyl	RCV000410558	SCV000489464	likely benign	Lynch syndrome 5	2016-10-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163801	SCV000685371	likely benign	Hereditary cancer-predisposing syndrome	2015-04-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000202109	SCV000917772	benign	not specified	2018-08-13	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3246G>A 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 observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 8-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 Ashkenazi Jewish origin. To our knowledge, no occurrence of c.3246G>A in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variant(s) have been reported (CHEK2 c.1263delT , p.Ser422fsX15), providing supporting evidence for a benign role. Three 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.
GeneDx	RCV000724321	SCV001757089	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798576	SCV002042046	likely benign	Breast and/or ovarian cancer	2020-09-23	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000202109	SCV002070930	likely benign	not specified	2021-03-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163801	SCV002527990	likely benign	Hereditary cancer-predisposing syndrome	2020-09-09	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000724321	SCV004011167	likely benign	not provided	2023-06-01	criteria provided, single submitter	clinical testing	MSH6: BP4, BP7
Myriad Genetics, Inc.	RCV000410558	SCV004018869	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000724321	SCV004221215	benign	not provided	2023-01-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535083	SCV004751139	likely benign	MSH6-related disorder	2019-03-20	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).
All of Us Research Program, National Institutes of Health	RCV003995283	SCV004835018	likely benign	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000202109	SCV000257245	uncertain significance	not specified		no assertion criteria provided	research
True Health Diagnostics	RCV000163801	SCV000886689	likely benign	Hereditary cancer-predisposing syndrome	2018-07-13	no assertion criteria provided	clinical testing