ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.842A>T (p.Asp281Val) (rs587781525)

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Total submissions: 21
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215048 SCV000273624 likely pathogenic Hereditary cancer-predisposing syndrome 2015-01-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting pathogenic classification,Well-characterized mutation at same position,Deficient protein function in appropriate functional assay(s),Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Database of Curated Mutations (DoCM) RCV000435739 SCV000507924 likely pathogenic Neoplasm of the breast 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418100 SCV000507925 likely pathogenic Uterine Carcinosarcoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428503 SCV000507926 likely pathogenic Squamous cell carcinoma of the skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438736 SCV000507927 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000417569 SCV000507928 likely pathogenic Chronic lymphocytic leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431328 SCV000507929 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441595 SCV000507930 likely pathogenic Neuroblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423894 SCV000507931 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434194 SCV000507932 likely pathogenic Renal cell carcinoma, papillary, 1 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440916 SCV000507933 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423186 SCV000507934 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433464 SCV000507935 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000443096 SCV000507936 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426125 SCV000507937 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432892 SCV000507938 likely pathogenic Multiple myeloma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000442104 SCV000507939 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425401 SCV000507940 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435682 SCV000507941 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
GeneDx RCV000161072 SCV000211806 pathogenic not provided 2014-06-11 criteria provided, single submitter clinical testing A pathogenic missense pathogenic variant displaying apparent mosaicism was detected, meaning the variant was detected in some, but not all, cells. This is a missense pathogenic variant, denoted TP53 c.842A>T at the cDNA level, p.Asp281Val (D281V) at the protein level, and results in the change of an Aspartic Acid to a Valine (GAC>GTC). This variant was observed in a patient with childhood osteosarcoma who had a family history of early-onset breast cancer (Chompret 2000). Three separate yeast based functional assays concluded that TP53 Asp281Val results in a transactivation-defective mutant phenotype while two additional functional assays, also yeast based, concluded that this mutation has a dominant negative effect and is unable to induce apoptosis (Monti 2007, Monti 2011, Pekova 2011). TP53 Asp281Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Aspartic Acid and Valine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Asp281Val occurs at a position that is highly conserved across species and is located within the DNA binding region and the regions of interaction with HIPK1, ZNF385A, FBXO42 and E4F1. In addition, In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the current evidence, we consider this variant to be pathogenic. This mutation appears to be mosaic, as the mutant allele was present but underrepresented in comparison to the normal allele. This result was confirmed using alternate, non-overlapping primers, making it unlikely that this result is due to preferential amplification of the normal allele. Therefore, this mutation is interpreted to be present in some, but not all, cells in this peripheral blood specimen. Neither Sanger nor Next Generation sequencing is a quantitative test; thus, it is not possible to determine more precisely the level of mosaicism in this specimen. Moreover, the level of mosaicism may be different in other tissues. As somatic mosaicism generally results from a post-zygotic event, parents and siblings are not likely at risk to carry this mosaic mutation. Germline mosaicism and transmission to the offspring of this patient, however, cannot be excluded. The following lifetime risks apply to individuals with germline TP53 mutations, and might be overestimates for individuals who are mosaic. A pathogenic variant in this gene is indicative of Li-Fraumeni syndrome (LFS), an autosomal dominant condition associated with a high risk for a broad range of childhood- and adult-onset cancers. The following core cancer types account for 70%-77% of LFS-associated tumors (in order of frequency): breast cancer, soft tissue sarcoma, brain tumors, osteosarcoma, and adrenocortical carcinoma (Gonzalez 2009, Olivier 2003, Ruijs 2010). Other types of cancer that have been reported to be associated with LFS include ovarian, gastrointestinal, pancreatic, genitourinary, skin, thyroid and lung cancers as well as leukemia, lymphoma, and neuroblastomas. Age-related and sex-specific cancer risks have been reported. According to one study, the overall risks for males with LFS to develop cancer by ages 16, 45, and 85 are estimated to be 19%, 41%, and 73%, respectively, whereas the risks for females are estimated to be 12%, 84%, and 100%, respectively (Chompret 2000). The higher penetrance in females is due to the high incidence of breast cancer, accounting for 80% of the cancers in the age group of 16 to 45 years (Chompret 2000). The majority of LFS-associated breast cancers are HER2/neu positive ductal carcinomas (Melhem-Bertrandt 2012). The most common types of sarcomas in LFS are rhabdomyosarcomas before age 5 and osteosarcomas at any age (Ognjanovic 2012). LFS is associated with many types of brain tumors including astrocytomas, glioblastomas, medulloblastomas and choroid plexus carcinomas, and they can occur in childhood or adulthood (Olivier 2003). Individuals with LFS who have been diagnosed with cancer have up to a 57% risk of a second primary cancer within 30 years of the first diagnosis and up to a 38% risk of a third primary diagnosis (Hisada 1998). Several studies have demonstrated that subsequent tumors often develop in the radiation field of the previously treated cancer (Chompret 2000, Hisada 1998). Approximately 24% of LFS cases result from a de novo, rather than inherited, variant in the TP53 gene (Chompret 2000).
Invitae RCV000799325 SCV000938982 pathogenic Li-Fraumeni syndrome 2018-11-05 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 281 of the TP53 protein (p.Asp281Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with osteosarcoma (PMID: 10864200). ClinVar contains an entry for this variant (Variation ID: 182968). Experimental studies have shown that this missense change disrupts the transcriptional transactivation activity of the TP53 protein (PMID: 12826609, 21343334, 9546439). This variant disrupts the p.Asp281 amino acid residue in TP53. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 15925506, 25293557, 23894400, 17572079), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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