ClinVar Genomic variation as it relates to human health

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19714490, 28693246, 34249677, 35016432, 24382691, 26425688, 21761402, 20436704, 10519380, 12779080, 18555592, 9115587, 21190917, 16969106, 12509970, 21665182, 28408749, 23484829, 17567834, 28526081, 18511570, 19556618, 26911350, 19711436, 30720243, 31081129, 31105275, 31447099, 32817165, 31742824, 33294277)

PVS1, PM1, PM2_SUP

This sequence change creates a premature translational stop signal (p.Arg342*) in the TP53 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 17567834, 19714490, 21761402, 24382691, 26911350). ClinVar contains an entry for this variant (Variation ID: 182970). For these reasons, this variant has been classified as Pathogenic.

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

The p.R342* pathogenic mutation (also known as c.1024C>T), located in coding exon 9 of the TP53 gene, results from a C to T substitution at nucleotide position 1024. This changes the amino acid from an arginine to a stop codon within coding exon 9. In one study, this mutation was detected in a 5-year-old male diagnosed with an adrenocortical tumor at 1.5 years of age and a medulloblastoma at 5 years of age. His 31-year-old unaffected father was also a carrier of the mutation (Trkova et al. Cancer. 2007 Aug;110(3):694-702). In another study, this alteration was identified in a 4-year-old who had been diagnosed with osteosarcoma, adenocarcinoma, and anaplastic rhabdomyosarcoma (Hettmer S et al. Cancer 2014 Apr;120(7):1068-75). It has also been reported in patients and/or families with breast and/or ovarian cancer (Melhem-Bertrandt A et al. Cancer 2012 Feb;118:908-13; Mannan AU et al. J. Hum. Genet. 2016 Jun;61:515-22; Shao D et al. Cancer Sci, 2020 Feb;111:647-657). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

PM2_Supporting+PVS1+PS4_Supporting

The TP53 c.1024C>T; p.Arg342Ter variant (rs730882029) is reported in the germline of at least two individuals with suspected Li Fraumeni syndrome (Hettmer 2014, Trkova 2007). The variant is listed as pathogenic by several sources in the ClinVar database (Variation ID: 182970), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is classified as pathogenic. References: Hettmer S et al. Anaplastic rhabdomyosarcoma in TP53 germline mutation carriers. Cancer. 2014 Apr 1;120(7):1068-75. Trkova M et al. Telomere length in peripheral blood cells of germline TP53 mutation carriers is shorter than that of normal individuals of corresponding age. Cancer. 2007 Aug 1;110(3):694-702.

The p.Arg342X variant in TP53 has been reported as a germline variant in more th an 15 individuals with TP53-associated cancers and as a somatic variant in more than 100 individuals (Fiszer-Maliszewska 2009, Schniederjan 2009, Lee 2010, Melh em-Bertrandt 2012, Hettmer 2014, Kandioler 2015, Mannan 2016, Smardova 2016, IAR C TP53 database [http://p53.iarc.fr/], COSMIC database). This variant has also b een reported in ClinVar (Variation ID# 182970) and was absent from large populat ion studies. In vitro functional studies provide some evidence that the p.Arg342 X variant may impact protein function by resulting in abnormal nuclear localizat ion (Trostel 2006). This nonsense variant leads to a premature termination codon at position 342 which is predicted to lead to a truncated or absent protein. He terozygous loss of function of the TP53 gene is an established disease mechanism in Li-Fraumeni syndrome. In summary, this variant meets criteria to be classifi ed as pathogenic for Li-Fraumeni syndrome in an autosomal dominant manner based upon frequency in affected individuals, absence from controls, and the predicted impact to the protein. ACMG/AMP Criteria applied: PVS1; PS4; PM2; PS3_Supportin g.

This variant changes 1 nucleotide in exon 10 of the TP53 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A functional study has shown the mutant protein to be mis-localized and unable to activate downstream targets (PMID: 16969106). This variant has been reported in multiple individuals affected with Li-Fraumeni syndrome-associated cancer, including childhood onset adrenocarcinoma, brain tumor and soft-tissue sarcoma (PMID: 17567834, 19711436, 19714490, 19556618, 24382691) and adult-onset breast and/or ovarian cancer (PMID: 21761402, 26911350). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of TP53 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.

Variant summary: TP53 c.1024C>T (p.Arg342X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251350 control chromosomes (gnomAD) but has been reported in the literature in multiple individuals affected with features of Li-Fraunemia syndrome such as breast and/or ovarian cancer, osteosarcoma, adenocarcinoma, adrenocortical carcinoma, foot fibrosarcoma and prostate cancer (Mannan_2016, Hettmer_2014, Fiszer-Maliszewska_2009, Wang_2013). These data indicate that the variant is very likely to be associated with disease. An experimental study using a cell system reports that this truncation impaired association with dynein motor complex and prevented p53 nuclear translocation (Trostel_2006). However, this does not allow convincing conclusions about the variant effect. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.