Submissions for variant NM_000179.3(MSH6):c.2241G>A (p.Leu747=)

gnomAD frequency: 0.00002  dbSNP: rs377722465

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000203714	SCV000260643	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-03	criteria provided, single submitter	clinical testing
Counsyl	RCV000410196	SCV000489578	likely benign	Lynch syndrome 5	2016-10-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000566554	SCV000662374	likely benign	Hereditary cancer-predisposing syndrome	2015-12-01	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	RCV000566554	SCV000685268	likely benign	Hereditary cancer-predisposing syndrome	2016-05-16	criteria provided, single submitter	clinical testing
GeneDx	RCV001355981	SCV000718710	likely benign	not provided	2019-12-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797677	SCV002041503	likely benign	not specified	2021-11-20	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000410196	SCV004018923	benign	Lynch syndrome 5	2023-03-28	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.
PreventionGenetics, part of Exact Sciences	RCV004541290	SCV004784623	likely benign	MSH6-related disorder	2021-11-19	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
All of Us Research Program, National Institutes of Health	RCV003997626	SCV004841894	likely benign	Lynch syndrome	2023-11-30	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355981	SCV001551021	likely benign	not provided		no assertion criteria provided	clinical testing	The MSH6 p.Leu747= variant was not identified in the literature nor was it identified in the following databases: COGR, Cosmic, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang University Database, Mismatch Repair Genes Variant Database, or the Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs377722465) as “With Likely benign allele”, in ClinVar (as likely benign by Invitae, Counsyl, Ambry Genetics, Color Genomics, and GeneDx), and Clinvitae (3x). The variant was identified in control databases in 14 of 245644 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (Non-Finnish) in 11 of 111156 chromosomes (freq: 0.0001), European (Finnish) in 2 of 22296 chromosomes (freq: 0.00009), and African in 1 of 15292 chromosomes (freq: 0.00007); it was not observed in the Ashkenazi Jewish, East Asian, Latino, Other, and South Asian populations. The p.Leu747= 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.