Submissions for variant NM_000179.3(MSH6):c.2418C>T (p.Ser806=)

gnomAD frequency: 0.00004  dbSNP: rs770992427

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162791	SCV000213269	likely benign	Hereditary cancer-predisposing syndrome	2014-10-22	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.
Eurofins Ntd Llc (ga)	RCV000590110	SCV000230041	uncertain significance	not provided	2014-10-07	criteria provided, single submitter	clinical testing
Invitae	RCV001082493	SCV000253094	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000590110	SCV000513692	likely benign	not provided	2020-05-27	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000178055	SCV000695814	likely benign	not specified	2019-09-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162791	SCV000911115	likely benign	Hereditary cancer-predisposing syndrome	2017-10-27	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162791	SCV002535738	likely benign	Hereditary cancer-predisposing syndrome	2021-05-29	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV003995219	SCV004840264	likely benign	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000590110	SCV001552846	likely benign	not provided		no assertion criteria provided	clinical testing	The MSH6 p.Ser806= variant was not identified in the literature nor was it identified in the COGR, UMD-LSDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, and or Insight Hereditary Tumors database. The variant was identified in dbSNP (ID: rs770992427) as "With other allele"), ClinVar (classified as likely benign by Ambry Genetics, Invitae, and GeneDx and as uncertain significance by two clinical laboratories: EGL Genetic Diagnostics and Integrated Genetics/Laboratory Corporation of America), and in Cosmic (1x in Haematopoietic and lymphoid tissue). The variant was identified in control databases in 5 of 276156 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 4 of 125786 chromosomes (freq: 0.00003), and East Asian in 1 of 18860 chromosomes (freq: 0.00005); it was not observed in the African, Other, Latino, Ashkenazi Jewish, Finnish, and or South Asian populations. The p.Ser806= 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, the c.2418C nucleotide is weakly conserved and 5 of 5 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.