Submissions for variant NM_000179.3(MSH6):c.189C>T (p.Ser63=)

dbSNP: rs917331457

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001088144	SCV000624700	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-10-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000565240	SCV000676111	likely benign	Hereditary cancer-predisposing syndrome	2016-09-25	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.
GeneDx	RCV000828064	SCV000969741	likely benign	not provided	2018-04-20	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.
Color Diagnostics, LLC DBA Color Health	RCV000565240	SCV001350505	likely benign	Hereditary cancer-predisposing syndrome	2018-11-12	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000565240	SCV002535679	likely benign	Hereditary cancer-predisposing syndrome	2020-11-28	criteria provided, single submitter	curation
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003316672	SCV004016015	likely benign	Lynch syndrome 5	2023-07-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001355050	SCV004830503	likely benign	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000565240	SCV005045488	likely benign	Hereditary cancer-predisposing syndrome	2024-03-22	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355050	SCV001549816	likely benign	Lynch syndrome		no assertion criteria provided	clinical testing	The MSH6 p.Ser63= variant was not identified in the literature nor was it identified in the following databases: dbSNP, ClinVar, COGR, Cosmic, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or the Insight Hereditary Tumors Database. The variant was identified in control databases in 1 of 108382 chromosomes at a frequency of 0.000009 (Genome Aggregation Database Feb 27, 2017), in the East Asian population in 1 of 6952 chromosomes (freq: 0.0001); it was not observed in the African, “Other”, Latino, European Non-Finnish, Ashkenazi Jewish, European Finnish, and South Asian populations. The variant was identified in our laboratory in 1 individual with ovarian cancer, co-occurring with a pathogenic BRCA2 variant (c.4631delA, p.Asn1544fsX24). The p.Ser63= 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 this variant meets our laboratory's criteria to be classified as likely benign.