Submissions for variant NM_000535.7(PMS2):c.1569C>G (p.Ser523=)

gnomAD frequency: 0.00560  dbSNP: rs141458772

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076816	SCV000108303	likely benign	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Synonymous variant with no effect on splicing or mRNA expression (treated with NMD inhibitor)
Invitae	RCV001079561	SCV000166379	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000127462	SCV000171029	benign	not specified	2013-10-21	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.
Ambry Genetics	RCV000162414	SCV000212753	likely benign	Hereditary cancer-predisposing syndrome	2014-08-21	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.
PreventionGenetics, part of Exact Sciences	RCV000127462	SCV000304723	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000612133	SCV000469727	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	RCV000162414	SCV000686140	benign	Hereditary cancer-predisposing syndrome	2015-04-24	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000127462	SCV000859782	benign	not specified	2018-03-07	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756559	SCV000884397	benign	not provided	2023-02-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000127462	SCV000888396	benign	not specified	2021-01-14	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000756559	SCV001155030	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	PMS2: BP4, BP7, BS2
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262171	SCV001439945	likely benign	Neoplasm of ovary	2019-01-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000127462	SCV002066495	benign	not specified	2020-08-18	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000127462	SCV002550710	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149755	SCV003837730	benign	Breast and/or ovarian cancer	2021-06-08	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000127462	SCV000691970	benign	not specified		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000612133	SCV000734564	likely benign	Lynch syndrome 4		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000612133	SCV000745840	likely benign	Lynch syndrome 4	2015-09-07	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000162414	SCV000805283	likely benign	Hereditary cancer-predisposing syndrome	2018-04-09	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357660	SCV001553188	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PMS2 p.Ser523= variant was identified in 2 of 1038 proband chromosomes (frequency: 0.002) from individuals or families with colorectal cancer (Borras 2013, Niessen 2009). The variant was also identified in the following databases: dbSNP (ID: rs141458772) as With Likely benign allele, ClinVar (classified as benign by Invitae, GeneDx, Prevention Genetics; as likely benign by InSight, Ambry Genetics), Insight Colon Cancer Gene Variant Database (1X class2), Insight Hereditary Tumors Database (1X class2). The variant was not identified in the COGR, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Databases. The variant was identified in control databases in 1721(31 homozygous) of 276904 chromosomes at a frequency of 0.006 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The silent p.Ser523= variant did not affect mRNA processing or stability by functional analysis at mRNA and protein level (Borras 2013). The p.Ser523= 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. However, 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this information is not predictive enough to assume pathogenicity. 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.
Clinical Genetics, Academic Medical Center	RCV000756559	SCV001920102	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000756559	SCV001952367	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000756559	SCV001964743	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000127462	SCV002036685	benign	not specified		no assertion criteria provided	clinical testing