ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.841G>A (p.Asp281Asn)

gnomAD frequency: 0.00001  dbSNP: rs764146326
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 22
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000824609 SCV000965512 pathogenic Li-Fraumeni syndrome 2023-09-29 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 281 of the TP53 protein (p.Asp281Asn). This variant is present in population databases (rs764146326, gnomAD 0.007%). This missense change has been observed in individual(s) with osteosarcoma and early-onset bilateral breast cancer (PMID: 17572079, 23894400). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 376586). 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. Experimental studies have shown that this missense change affects TP53 function (PMID: 11896595, 12826609, 19850740). 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: 10864200, 12826609, 15925506, 25293557; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV002446642 SCV002679393 pathogenic Hereditary cancer-predisposing syndrome 2022-06-16 criteria provided, single submitter clinical testing The p.D281N pathogenic mutation (also known as c.841G>A), located in coding exon 7 of the TP53 gene, results from a G to A substitution at nucleotide position 841. The aspartic acid at codon 281 is replaced by asparagine, an amino acid with highly similar properties. This variant has been reported in multiple individuals meeting clinical criteria for Li-Fraumeni synrome (LFS) (Salmon A et al. Clin Oncol (R Coll Radiol). 2007 Sep;19:490-3; Mitchell G et al. PLoS One. 2013 Jul;8:e69026). This variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000824609 SCV004848616 likely pathogenic Li-Fraumeni syndrome 2022-02-09 criteria provided, single submitter clinical testing The p.Asp281Asn variant in TP53 has been reported as a de novo occurrence in an individual with early onset bilateral breast cancer and an individual with osteosarcoma (Salmon 2007 PMID: 17572079, Mitchell 2013 PMID: 23894400) and has also been reported in 1 individual with early onset breast cancer (32 y.o) and 1 individual with unspecified sarcoma in the TP53 database (https://tp53.isb-cgc.org/). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 376586) and was identified in 0.006% (1/16252) of African/African-American chromosomes in gnomAD (https://gnomad.broadinstitute.org/). In vitro functional studies support an impact of this variant on protein function (Monti 2002 PMID: 11896595) and computational prediction tools and conservation analysis suggest that this variant may impact the protein. Of note, this variant occurs in the DNA binding domain of TP53, where multiple pathogenic variants have been identified. Additional variants involving this codon (p.Asp281Val, p.Asp2818Gly) have been identified (as a de novo occurrence in some instances) in individuals with Li-Fraumeni-associated cancers. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Li-Fraumeni syndrome. ACMG/AMP criteria applied: PS4_Moderate, PM6_Supporting, PM2_Supporting, PS3_Supporting, PP3, PM5_Supporting.
Database of Curated Mutations (DoCM) RCV000429505 SCV000507906 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439749 SCV000507907 likely pathogenic Papillary renal cell carcinoma type 1 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000422096 SCV000507908 likely pathogenic Neuroblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428837 SCV000507909 likely pathogenic Squamous cell carcinoma of the skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438896 SCV000507910 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421233 SCV000507911 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431489 SCV000507912 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000443405 SCV000507913 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424002 SCV000507914 likely pathogenic B-cell chronic lymphocytic leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434267 SCV000507915 likely pathogenic Ovarian serous cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000443489 SCV000507916 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426863 SCV000507917 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437075 SCV000507918 likely pathogenic Uterine carcinosarcoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000442054 SCV000507919 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426180 SCV000507920 likely pathogenic Gastric adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436424 SCV000507921 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418705 SCV000507922 likely pathogenic Multiple myeloma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428968 SCV000507923 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne RCV000785452 SCV000924024 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.