Submissions for variant NM_000179.3(MSH6):c.1449G>T (p.Val483=)

gnomAD frequency: 0.00037  dbSNP: rs35590297

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001084470	SCV000166209	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000202140	SCV000170353	benign	not specified	2014-02-25	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.
Ambry Genetics	RCV000126826	SCV000213008	likely benign	Hereditary cancer-predisposing syndrome	2014-08-25	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.
Color Diagnostics, LLC DBA Color Health	RCV000126826	SCV000685194	likely benign	Hereditary cancer-predisposing syndrome	2015-06-15	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000600196	SCV000744291	likely benign	Lynch syndrome 5	2017-06-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679214	SCV000805843	likely benign	not provided	2017-11-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679214	SCV000888239	benign	not provided	2023-06-13	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000679214	SCV001152290	likely benign	not provided	2023-02-01	criteria provided, single submitter	clinical testing	MSH6: BP4, BP7
Illumina Laboratory Services, Illumina	RCV000600196	SCV001299858	uncertain significance	Lynch syndrome 5	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798401	SCV002042034	likely benign	Breast and/or ovarian cancer	2023-03-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000202140	SCV002070095	likely benign	not specified	2021-11-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000126826	SCV002535625	likely benign	Hereditary cancer-predisposing syndrome	2021-04-26	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000202140	SCV002760659	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997396	SCV004843599	likely benign	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000202140	SCV000257211	likely benign	not specified		no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000600196	SCV000734213	likely benign	Lynch syndrome 5		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000600196	SCV000745649	likely benign	Lynch syndrome 5	2016-09-05	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000126826	SCV000886688	likely benign	Hereditary cancer-predisposing syndrome	2018-08-03	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356260	SCV001551377	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH6 p.Val483= variant was not identified in the literature. The variant was identified in dbSNP (ID: rs35590297) as "With other allele", ClinVar (classified as benign by Invitae and GeneDx; as likely benign by seven submitters), and in UMD-LSDB (2x as unclassified variant). The variant was identified in control databases in 92 of 276872 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 3 of 24024 chromosomes (freq: 0.0001), Other in 3 of 6462 chromosomes (freq: 0.0005), Latino in 4 of 34382 chromosomes (freq: 0.0001), European in 75 of 126426 chromosomes (freq: 0.0006), Finnish in 7 of 25794 chromosomes (freq: 0.0003); it was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. The p.Val483= 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.
Clinical Genetics, Academic Medical Center	RCV000679214	SCV001922359	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000679214	SCV001951063	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000679214	SCV001977948	likely benign	not provided		no assertion criteria provided	clinical testing