Submissions for variant NM_000179.3(MSH6):c.3265T>C (p.Leu1089=)

gnomAD frequency: 0.00096  dbSNP: rs34490141

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164765	SCV000215441	benign	Hereditary cancer-predisposing syndrome	2014-07-11	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081375	SCV000259406	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164765	SCV000685381	likely benign	Hereditary cancer-predisposing syndrome	2015-04-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589050	SCV000695848	benign	not provided	2016-01-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589050	SCV000888270	benign	not provided	2018-03-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000589050	SCV001834059	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818376	SCV002070932	likely benign	not specified	2021-04-06	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000164765	SCV002528002	benign	Hereditary cancer-predisposing syndrome	2021-01-04	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150018	SCV003837650	likely benign	Breast and/or ovarian cancer	2021-06-21	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003316028	SCV004016008	benign	Lynch syndrome 5	2023-07-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001818376	SCV004243100	likely benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356967	SCV001552274	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 p.Leu1089= variant was not identified in the literature nor was it identified in the UMD-LSDB database. The variant was identified in dbSNP (rs34490141) as “with other allele and ClinVar (classified as benign by Invitae, Ambry Genetics, Integrated Genetics and 1 other submitter; and as likely benign by Color). The variant was identified in control databases in 90 of 282,832 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 84 of 24,974 chromosomes (freq: 0.003, increasing the likelihood this could be a low frequency benign variant), Latino in 4 of 35,422 chromosomes (freq: 0.0001), South Asian in 1 of 30,616 chromosomes (freq: 0.00003), and European in 1 of 129,162 chromosomes (freq: 0.000008), while it was not observed in the Ashkenazi Jewish, East Asian, Finnish or Other populations. The p.Leu1089= 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. The variant occurs at a non-highly conserved nucleotide outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing; this is not very predictive of pathogenicity. 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.