ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.455C>T (p.Pro152Leu) (rs587782705)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132156 SCV000187230 pathogenic Hereditary cancer-predisposing syndrome 2017-07-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Deficient protein function in appropriate functional assay(s),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
CSER_CC_NCGL; University of Washington Medical Center RCV000168122 SCV000700113 pathogenic Li-Fraumeni syndrome 2016-10-01 criteria provided, single submitter research Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 60 year old female diagnosed with colon cancer at age 39 and a family history of colon polyps. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Equipe Genetique des Anomalies du Developpement,Université de Bourgogne RCV000677669 SCV000803809 pathogenic Li-Fraumeni syndrome 1 2016-01-25 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement,Université de Bourgogne RCV000755703 SCV000883137 pathogenic Familial cancer of breast 2018-11-21 criteria provided, single submitter clinical testing
Invitae RCV000168122 SCV000218779 pathogenic Li-Fraumeni syndrome 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 152 of the TP53 protein (p.Pro152Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs587782705, ExAC 0.02%). This variant has been reported in multiple families with Li-Fraumeni-like (LFL) syndrome (PMID: 17606709) and in individuals affected with adrenocortical cancer, breast cancer, gastric cancer or colorectal cancer and melanoma (PMID: 7966399, 21552135, 26086041, 21934104) one of whom was affected with Li-Fraumeni syndrome. ClinVar contains an entry for this variant (Variation ID: 142766). Experimental studies indicate that this missense change severely reduces the DNA-binding activity of the TP53 protein to less than 25% of normal and it is non-functional in a transactivation assay (PMID: 20128691, 21343334, 12826609, 20128691 ). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000168122 SCV000710875 pathogenic Li-Fraumeni syndrome 2017-10-19 criteria provided, single submitter clinical testing The p.Pro152Leu variant in TP53 has been reported in at least 10 individuals wit h TP53-associated cancers and segregated with disease in at least 5 affected rel atives from 3 families (Varley 1999, Dickens 2005, Bougeard 2008, Tabori 2007, M asciari 2011, Yurgelun 2015, IARC TP53 database, http://p53.iarc.fr/, ClinVar, V ariation ID: 142766). It has also been identified in several unaffected adult re latives (Varley 1999, Dickens 2005, Yurgelun 2015), suggesting reduced penetranc e for this variant. In vitro functional studies provide evidence that the p.Pro1 52Leu variant may impact protein function by severely reducing its DNA-binding a ctivity (Malcikova 2010, Monti 2011). This variant has been identified in 1/1115 66 European and 1/9848 Ashkenazi Jewish chromosomes by the Genome Aggregation Da tabase (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs587782705). In summary , this variant meets criteria to be classified as pathogenic for Li-Fraumeni syn drome in an autosomal dominant manner based upon multiple reports in affected in dividuals, segregation studies, low frequency in controls, and functional eviden ce. ACMG/AMP Criteria applied: PS4_Strong, PP1_Moderate, PM2, PS3_Supporting, PP 3 (Richards 2015).
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000583667 SCV000692088 pathogenic not provided no assertion criteria provided clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000132156 SCV000266135 pathogenic Hereditary cancer-predisposing syndrome 2015-11-20 criteria provided, single submitter clinical testing

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