Submissions for variant NM_000179.3(MSH6):c.642C>T (p.Tyr214=)

gnomAD frequency: 0.07457  dbSNP: rs1800937

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000030277	SCV000108237	no known pathogenicity	Lynch syndrome	2013-09-05	reviewed by expert panel	research	MAF >1%
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030277	SCV000052944	benign	Lynch syndrome	2011-08-18	criteria provided, single submitter	clinical testing	Converted during submission to Benign.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035327	SCV000058975	benign	not specified	2011-09-21	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000035327	SCV000110163	benign	not specified	2013-02-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000132355	SCV000187444	benign	Hereditary cancer-predisposing syndrome	2014-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV000132355	SCV000292091	benign	Hereditary cancer-predisposing syndrome	2022-01-02	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000035327	SCV000302882	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000605855	SCV000430954	benign	Lynch syndrome 5	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001668142	SCV000604266	benign	not provided	2023-11-29	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000605855	SCV000744288	benign	Lynch syndrome 5	2015-09-21	criteria provided, single submitter	clinical testing
Invitae	RCV000860472	SCV001000531	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001668142	SCV001888486	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27884173, 12547705, 24689082, 23588873)
Sema4, Sema4	RCV000132355	SCV002536337	benign	Hereditary cancer-predisposing syndrome	2020-02-24	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002496466	SCV002808115	benign	Endometrial carcinoma; Lynch syndrome 5; Mismatch repair cancer syndrome 3	2021-12-13	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000605855	SCV004015985	benign	Lynch syndrome 5	2023-07-07	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000035327	SCV000257304	benign	not specified		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353937	SCV000592571	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Tyr214Tyr variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located near a splice junction. It is listed in dbSNP database as coming from a "clinical source" (ID#: rs1800937) with a global minor allele frequency (MAF) of 0.050, being identified in varying frequencies in various ethnic groups from the HapMap project. It has been reported in the literature in 69/1520 proband chromosomes of individuals from HNPCC and HNPCC-like families, as well as in breast cancer families with colorectal and/ or endometrial cancer. It was also reported in 22/1336 control chromosomes evaluated (Charames_2000_11153917, de Abajo_2005_16270383, Dovrat_2005_16341805, Hendriks_2003_12547705, Kolodner_1999_10537275, Perez-Cabornero_2009_19250818, Peterlongo_2003_14520694, Plaschke_2000_10699937, Vahteristo_2005_15805151, Verma_1999_10507723). In addition, the variant was also identified in the UMD database (x66) as a neutral alteration, as well as in the InSiGHT and Exome Server databases. In summary, based on the above information, this variant is classified as Benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000605855	SCV000734211	benign	Lynch syndrome 5		no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000132355	SCV000788057	benign	Hereditary cancer-predisposing syndrome	2018-02-27	no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000035327	SCV001906134	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000035327	SCV001919900	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000035327	SCV001956166	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000035327	SCV001977847	benign	not specified		no assertion criteria provided	clinical testing