Submissions for variant NM_000179.3(MSH6):c.1773A>G (p.Pro591=)

gnomAD frequency: 0.00002  dbSNP: rs752239740

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000456919	SCV000561472	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000569283	SCV000662349	likely benign	Hereditary cancer-predisposing syndrome	2016-01-19	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	RCV000569283	SCV000685226	likely benign	Hereditary cancer-predisposing syndrome	2016-03-29	criteria provided, single submitter	clinical testing
GeneDx	RCV001683522	SCV001896861	benign	not provided	2015-09-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002230861	SCV002511419	likely benign	not specified	2022-04-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001683522	SCV004701984	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	MSH6: BP4, BP7
All of Us Research Program, National Institutes of Health	RCV004002162	SCV004840074	likely benign	Lynch syndrome	2023-11-30	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357565	SCV001553071	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH6 p.Pro591= variant was not identified in the literature nor was it identified in the COGR, Cosmic, UMD-LSDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors database. The variant was identified in dbSNP (ID: rs752239740 as "With Likely benign allele") and ClinVar (3x as likely benign by Invitae, Ambry Genetics, and Color Genomics). The variant was identified in control databases in 9 of 245998 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 7 of 111488 chromosomes (freq: 0.00006) and Finnish in 2 of 22300 chromosomes (freq: 0.00009); it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, or South Asian populations. The p.Pro591= 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 outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% 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. This variant is classified as a variant of uncertain significance.