Submissions for variant NM_000546.6(TP53):c.842A>T (p.Asp281Val)

dbSNP: rs587781525

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
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).
Ambry Genetics	RCV000215048	SCV000273624	likely pathogenic	Hereditary cancer-predisposing syndrome	2015-01-29	criteria provided, single submitter	clinical testing	The p.D281V variant (also known as c.842A>T), located in coding exon 7 of the TP53 gene, results from an A to T substitution at nucleotide position 842. The aspartic acid at codon 281 is replaced by valine, an amino acid with highly dissimilar properties. This variant was first described in an 18 year old male with osteosarcoma (Chompret A, Br. J. Cancer 2000 Jun; 82(12):1932-7). Parental testing in this family failed to detect the p.D281V mutation, indicating that p.D281V likely occurred as a de novo event in the affected individual. In addition, other alterations impacting codon 281 have been reported as pathogenic (Krutilkova V et al. Eur. J. Cancer 2005; 41:1597-603; Salmon A et al. Clin Oncol (R Coll Radiol). 2007 Sep;12(7):490-3; Petitjean A et al. IARC TP53 database [version R16, November 2012]. Hum Mutat. 2007 Jun;28(6):622-9). Functional studies in yeast have demonstrated a compete loss of transactivation capacity and a strong dominant negative effect for this alteration (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Flaman JM, Oncogene 1998 Mar; 16(10):1369-72; Monti P, Mol. Cancer Res. 2011 Mar; 9(3):271-9.). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV000799325	SCV000938982	pathogenic	Li-Fraumeni syndrome	2022-12-15	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp281 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15925506, 17390010, 17572079, 21305319, 23894400, 25293557). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. ClinVar contains an entry for this variant (Variation ID: 182968). This missense change has been observed in individual(s) with osteosarcoma (PMID: 10864200). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 281 of the TP53 protein (p.Asp281Val).
Genome-Nilou Lab	RCV000215048	SCV002582348	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288706	SCV002583008	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Database of Curated Mutations (DoCM)	RCV000435739	SCV000507924	likely pathogenic	Breast neoplasm	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	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000417569	SCV000507928	likely pathogenic	B-cell 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	Papillary renal cell carcinoma type 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