Submissions for variant NM_000179.3(MSH6):c.1209C>G (p.Leu403=)

gnomAD frequency: 0.00001  dbSNP: rs748603803

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000206756	SCV000261447	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000222978	SCV000274737	likely benign	Hereditary cancer-predisposing syndrome	2015-08-13	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.
Counsyl	RCV000411303	SCV000489502	likely benign	Lynch syndrome 5	2016-10-13	criteria provided, single submitter	clinical testing
GeneDx	RCV000423522	SCV000518264	likely benign	not specified	2016-09-19	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	RCV000222978	SCV000685180	likely benign	Hereditary cancer-predisposing syndrome	2017-04-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798688	SCV002042032	likely benign	Breast and/or ovarian cancer	2020-12-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000423522	SCV002074275	likely benign	not specified	2022-01-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001355678	SCV002774194	likely benign	not provided	2021-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000411303	SCV004018858	benign	Lynch syndrome 5	2023-03-27	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.
All of Us Research Program, National Institutes of Health	RCV003997650	SCV004835320	likely benign	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355678	SCV001550631	likely benign	not provided		no assertion criteria provided	clinical testing	The MSH6 p.Leu403= variant was identified in 1 of 3786 proband chromosomes (frequency: 0.0003) from individuals or families with ovarian cancer (Pal 2012). The variant was also identified in dbSNP (ID: rs748603803) as "With Likely benign allele", ClinVar (classified as likely benign by Invitae, Ambry Genetics, Counsyl, GeneDx and Color). The variant was not identified in UMD-LSDB database. The variant was identified in control databases in 3 of 246058 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 3 of 111550 chromosomes (freq: 0.00003); it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Leu403= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.