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

gnomAD frequency: 0.00001  dbSNP: rs764146326

Total submissions: 22

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