Submissions for variant NM_000179.3(MSH6):c.1875C>T (p.Ser625=)

gnomAD frequency: 0.00010  dbSNP: rs63749886

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074695	SCV000107899	likely benign	Lynch syndrome	2018-10-18	reviewed by expert panel	curation	Multifactorial likelihood analysis posterior probability 0.001-0.049 (0.029)
Ambry Genetics	RCV000162760	SCV000213237	likely benign	Hereditary cancer-predisposing syndrome	2015-01-22	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV001084121	SCV000252626	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000074695	SCV000430965	uncertain significance	Lynch syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162760	SCV000690231	benign	Hereditary cancer-predisposing syndrome	2015-10-29	criteria provided, single submitter	clinical testing
Counsyl	RCV000663035	SCV000786072	likely benign	Lynch syndrome 5	2018-02-23	criteria provided, single submitter	clinical testing
Mendelics	RCV000074695	SCV000837890	likely benign	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759847	SCV000889463	benign	not provided	2020-10-27	criteria provided, single submitter	clinical testing
Mendelics	RCV000663035	SCV001135812	likely benign	Lynch syndrome 5	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000504553	SCV001361761	likely benign	not specified	2020-11-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000759847	SCV001884172	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162760	SCV002535672	likely benign	Hereditary cancer-predisposing syndrome	2021-05-31	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000759847	SCV002544035	likely benign	not provided	2022-05-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000663035	SCV004018958	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492398	SCV004239302	likely benign	Breast and/or ovarian cancer	2023-03-03	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000504553	SCV004243090	likely benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353534	SCV000592593	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Ser625Ser variant was identified by Vahteristo, 2005 in a breast or colorectal carcinoma patient with family history of cancer. The variant was also identified in dbSNP (ID: rs63749886) “With uncertain significance”, “Mismatch Repair Genes Variant Database”, “Zhejiang Colon Cancer Database”, the ClinVar database 1x with “uncertain significance”, InSiGHT Colon Cancer Gene Variant Database 1X as an “unknown variant” and UMD 1 X as a “neutral” variant,. This variant was also identified in the the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 19 of 120346 (European (Finnish and non-Finnish) and Latino) alleles (frequency: 0.00016), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Ser625Ser 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 addition, this variant was found in our laboratory to co-occur in with a known pathogenic variant c.3957dupA, increasing the likelihood that this variant does not have clinical significance. In summary, based on the above information, this variant meets our laboratories criteria to be classified as benign.