Submissions for variant NM_000179.3(MSH6):c.1345C>T (p.Leu449=)

gnomAD frequency: 0.00429  dbSNP: rs3136333

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030260	SCV000052927	benign	Lynch syndrome	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Benign.
GeneDx	RCV000153513	SCV000170352	benign	not specified	2014-01-09	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	RCV000132062	SCV000187125	benign	Hereditary cancer-predisposing syndrome	2014-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as 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)	RCV000153513	SCV000203036	benign	not specified	2014-03-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524106	SCV000260473	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132062	SCV000685187	benign	Hereditary cancer-predisposing syndrome	2015-04-22	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000153513	SCV000805841	benign	not specified	2017-01-30	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001705607	SCV001158619	benign	not provided	2021-05-08	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001139681	SCV001299857	benign	Lynch syndrome 5	2018-01-31	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Genetic Services Laboratory, University of Chicago	RCV000153513	SCV002070927	benign	not specified	2021-11-23	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149585	SCV003837641	benign	Breast and/or ovarian cancer	2021-09-21	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001139681	SCV004015988	benign	Lynch syndrome 5	2023-07-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV001705607	SCV005243561	benign	not provided		criteria provided, single submitter	not provided
Mayo Clinic Laboratories, Mayo Clinic	RCV000153513	SCV000691925	benign	not specified		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356668	SCV001551902	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH6 p.Leu449= variant was not identified in the literature. The variant was identified in dbSNP (ID: rs3136333) as "With Benign allele", ClinVar (classified as benign by Invitae, Ambry Genetics and six other submitters), and in UMD-LSDB (2x as neutral) database. The variant was identified in control databases in 351 of 276748 chromosomes (2 homozygous) at a frequency of 0.001, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 341 of 24010 chromosomes (2 homozygous, freq: 0.01), Other in 1 of 6464 chromosomes (freq: 0.0002), Latino in 5 of 34396 chromosomes (freq: 0.0002), European in 3 of 126476 chromosomes (freq: 0.00002), and South Asian in 1 of 30782 chromosomes (freq: 0.00003), while the variant was not observed in the Ashkenazi Jewish, East Asian, or Finnish populations. The p.Leu449= 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. However, 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predicts a greater that 10% difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000153513	SCV001808340	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV001705607	SCV001905945	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001705607	SCV001918697	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000153513	SCV001951452	benign	not specified		no assertion criteria provided	clinical testing