ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1569C>G (p.Ser523=) (rs141458772)

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Total submissions: 18
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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 2020-12-08 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 In silico models in agreement (benign);Synonymous alterations with insufficient evidence to classify as benign
PreventionGenetics,PreventionGenetics RCV000127462 SCV000304723 benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000612133 SCV000469727 likely benign Hereditary nonpolyposis colorectal cancer type 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000127462 SCV000601825 benign not specified 2016-11-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162414 SCV000686140 benign Hereditary cancer-predisposing syndrome 2015-04-24 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000127462 SCV000859782 benign not specified 2018-03-07 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282354 SCV000884397 likely benign none provided 2019-12-18 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000756559 SCV000888396 benign not provided 2016-11-23 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000756559 SCV001155030 likely benign not provided 2018-07-01 criteria provided, single submitter clinical testing
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
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 Hereditary nonpolyposis colorectal cancer type 4 no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000612133 SCV000745840 likely benign Hereditary nonpolyposis colorectal cancer type 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.

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