ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.586C>T (p.Arg196Ter) (rs397516435)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000412710 SCV000605426 pathogenic not provided 2017-05-10 criteria provided, single submitter clinical testing The TP53 c.586C>T, p.Arg196Ter variant (rs397516435) has been reported in multiple individuals diagnosed with Li-Fraumeni syndrome (Bendig 2004, Grayson 1994, Vahteristo 2001, Villani 2016). It is observed in the Genome Aggregation Database general population database at a frequency of 0.00041 percent. The variant introduces a premature termination codon, and is predicted to result in a truncated protein or an absent transcript. Based on the above information, the variant is classified as pathogenic. References: Bendig I et al. Identification of novel TP53 mutations in familial and sporadic cancer cases of German and Swiss origin. Cancer Genet Cytogenet. 2004; 154(1):22-6. Grayson G et al. Novel germline mutation of the p53 tumor suppressor gene in a child with incidentally discovered adrenal cortical carcinoma. Am J Pediatr Hematol Oncol. 1994; 16(4):341-7. Vahteristo P et al. p53, CHK2, and CHK1 genes in Finnish families with Li-Fraumeni syndrome: further evidence of CHK2 in inherited cancer predisposition. Cancer Res. 2001; 61(15):5718-22. Villani A et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study. Lancet Oncol. 2016; 17(9):1295-305.
Ambry Genetics RCV000131510 SCV000186503 pathogenic Hereditary cancer-predisposing syndrome 2017-02-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
GeneDx RCV000412710 SCV000490858 pathogenic not provided 2018-10-18 criteria provided, single submitter clinical testing This pathogenic variant is denoted TP53 c.586C>T at the cDNA level and p.Arg196Ter (R196X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been identified in several individuals meeting clinical diagnostic criteria for Li-Fraumeni syndrome, Chompret criteria for TP53 testing, or with early-onset/multiple primary cancer diagnoses, with a de novo occurrence in at least one individual (Grayson 1994, Vahteristo 2001, Bendig 2004, Trkova 2007, Pinto 2009, Mitchell 2013, Rath 2013, Llovet 2017). Functional studies by Malcikova et al. (2010) demonstrated that TP53 Arg196Ter significantly impacts DNA binding and transcriptional activation (Malcikova 2010). We therefore consider this variant to be pathogenic.
Genetic Services Laboratory, University of Chicago RCV000205265 SCV000597519 pathogenic Li-Fraumeni syndrome 2017-01-26 criteria provided, single submitter clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785329 SCV000923897 pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
Invitae RCV000205265 SCV000260299 pathogenic Li-Fraumeni syndrome 2018-07-16 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg196*) in the TP53 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs397516435, ExAC 0.001%). This variant has been reported in multiple individuals and families affected with Li-Fraumeni or Li-Fraumeni-like syndrome (PMID: 7978053, 11479205, 15381368, 19468865, 21552135, 23894400). This variant is also known as 711C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 43589). Loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000205265 SCV000060186 pathogenic Li-Fraumeni syndrome 2018-03-30 criteria provided, single submitter clinical testing The p.Arg196X variant in TP53 has been reported in >10 individuals with Li-Fraum eni syndrome, with a de novo occurrence in at least 1 individual, and segregated with disease in 1 affected relative from 1 family (Grayson 1994, Vahteristo 200 1, Bendig 2004, Trkova 2007, Pinto 2009, Masciari 2011, Mitchell 2013, Meric-Ber nstam 2016, Villani 2016, LMM data). It has also been identified in 1/111706 Eu ropean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.bro adinstitute.org; dbSNP rs397516435); however this frequency is low enough to be consistent with the frequency of Li-Fraumeni syndrome in the general population. This nonsense variant leads to a premature termination codon at position 196, w hich is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the TP53 gene is an established disease mechanism in individuals wi th Li-Fraumeni syndrome. In summary, this variant meets criteria to be classifie d as pathogenic for Li-Fraumeni syndrome in an autosomal dominant manner. ACMG/A MP criteria applied: PVS1, PM2, PM6.

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