Submissions for variant NM_000535.7(PMS2):c.1557T>C (p.Tyr519=)

gnomAD frequency: 0.00992  dbSNP: rs6972869

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130271	SCV000185116	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.
Eurofins Ntd Llc (ga)	RCV000174013	SCV000225237	benign	not specified	2014-08-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524438	SCV000262045	benign	Hereditary nonpolyposis colorectal neoplasms	2025-02-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000205619	SCV000469728	likely benign	Lynch syndrome 4	2018-01-12	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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Color Diagnostics, LLC DBA Color Health	RCV000130271	SCV000686138	benign	Hereditary cancer-predisposing syndrome	2015-04-22	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000174013	SCV000806178	benign	not specified	2017-02-02	criteria provided, single submitter	clinical testing
GeneDx	RCV001675630	SCV001895865	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000174013	SCV002550714	benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000205619	SCV004016585	benign	Lynch syndrome 4	2023-07-07	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000130271	SCV005205785	benign	Hereditary cancer-predisposing syndrome	2024-07-16	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV001675630	SCV005224541	likely benign	not provided		criteria provided, single submitter	not provided
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001675630	SCV005879048	benign	not provided	2024-04-25	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000130271	SCV000788105	likely benign	Hereditary cancer-predisposing syndrome	2017-10-26	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357173	SCV001552547	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PMS2 p.Tyr519= variant was identified in 1 of 792 proband chromosomes (frequency: 0.001) from Dutch individuals or families with MMR-deficient cancer, or positive family history/young age of onset for CRC, endometrial or other Lynch associated cancer (van der Klift_2016_27435373). In this study, the variant showed no mRNA aberratiom or allelic imbalance using cultured lymphocytes. The variant was also identified in dbSNP (ID: rs6972869) “With other allele”, ClinVar (classified benign by Ambry Genetics, EGL Genetic Diagnostics (Eurofins Clinical Diagnostics) and Invitae, and likely benign by Illumina), and Clinvitae (4x), but was not identified in Genesight-COGR, Cosmic, MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was identified in control databases in 867 (15 homozygous) of 277080 chromosomes at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 824 (15 homozygous) of 23990 chromosomes (freq: 0.03), Other in 8 of 6464 chromosomes (freq: 0.001), Latino in 25 of 34418 chromosomes (freq: 0.0007), European Non-Finnish in 10 of 126632 chromosomes (freq: 0.00008), while not observed in the Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Tyr519= 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 benign.
Clinical Genetics, Academic Medical Center	RCV000174013	SCV001917433	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000174013	SCV001954791	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000174013	SCV002035952	benign	not specified		no assertion criteria provided	clinical testing