Submissions for variant NM_000179.3(MSH6):c.178T>C (p.Leu60=)

gnomAD frequency: 0.00006  dbSNP: rs35819209

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001080064	SCV000166214	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000212625	SCV000170366	benign	not specified	2014-03-03	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	RCV000126838	SCV000214176	likely benign	Hereditary cancer-predisposing syndrome	2015-01-06	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	RCV000412370	SCV000488979	likely benign	Lynch syndrome 5	2016-07-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000126838	SCV000537511	likely benign	Hereditary cancer-predisposing syndrome	2015-12-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679218	SCV000805849	likely benign	not provided	2017-04-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679218	SCV000889459	likely benign	not provided	2022-08-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212625	SCV001362734	likely benign	not specified	2019-03-01	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.178T>C 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 variant allele was found at a frequency of 6.4e-05 in 157094 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MSH6 causing Lynch Syndrome (6.4e-05 vs 0.00014), allowing no conclusion about variant significance. c.178T>C has been reported in the literature in individuals affected with colon cancer. This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six 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 likely benign.
Sema4, Sema4	RCV000126838	SCV002535661	likely benign	Hereditary cancer-predisposing syndrome	2020-11-20	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212625	SCV002552271	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000412370	SCV004018974	benign	Lynch syndrome 5	2023-03-29	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.
CeGaT Center for Human Genetics Tuebingen	RCV000679218	SCV004146075	likely benign	not provided	2023-01-01	criteria provided, single submitter	clinical testing	MSH6: BP4, BP7
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000126838	SCV004228098	likely benign	Hereditary cancer-predisposing syndrome	2023-07-27	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356200	SCV001551304	likely benign	Lynch syndrome		no assertion criteria provided	clinical testing	The MSH6 p.Leu60= variant was identified in 1 of 2132 proband chromosomes (frequency: 0.00046) from individuals or families with colorectal cancer (Hampel 2005). The variant was also identified in the following databases: dbSNP (ID: rs35819209) as “With Likely benign allele”, ClinVar and Clinvitae (6x as benign by Invitae and GeneDx, and as likely benign by Ambry Genetics, Counsyl, Color Genomics and Quest diagnostics), Insight Colon Cancer Gene Variant Database (1x) and Insight Hereditary Tumors Database (2x). The variant was not identified in the COGR, Cosmic, MutDB, UMD-LSDB, Zhejiang University Database or the Mismatch Repair Genes Variant Database. The variant was identified in control databases in 10 of 157094 chromosomes at a frequency of 0.000064 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European Non-Finnish in 9 of 66828 chromosomes (freq: 0.00013) and Ashkenazi Jewish in 1 of 6288 chromosomes (freq: 0.00016); it was not observed in the African, “Other”, Latino, East Asian, European Finnish or South Asian populations. The p.Leu60Leu 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, HumanSpliceFinder) 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.