Submissions for variant NM_000546.6(TP53):c.715A>G (p.Asn239Asp)

dbSNP: rs876660807

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000223044	SCV000278521	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-05	criteria provided, single submitter	clinical testing	The p.N239D pathogenic mutation (also known as c.715A>G), located in coding exon 6 of the TP53 gene, results from an A to G substitution at nucleotide position 715. The asparagine at codon 239 is replaced by aspartic acid, an amino acid with highly similar properties. This alteration has been reported as a somatic mutation 52 times in various tumors, but not as a germline mutation by the IARC TP53 database (Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum Mutat. 2007 Jun;28(6):622-9). In addition, this alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). This mutation 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 8;100(14):8424-9; Flaman JM, et al. Oncogene 1998 Mar; 16(10):1369-72; Fouquet C, et al. Clin. Cancer Res. 2004 May; 10(10):3479-89). 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). In addition, based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Cho Y, Science 1994 Jul; 265(5170):346-55; Martin A et al. Hum. Mutat. 2002 Feb; 19(2):149-64). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000560536	SCV000629857	uncertain significance	Li-Fraumeni syndrome	2025-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 239 of the TP53 protein (p.Asn239Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and ovarian cancer, or colorectal cancer (PMID: 28135145, 32885271). ClinVar contains an entry for this variant (Variation ID: 234036). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 9546439, 12826609, 15161705, 20407015, 29979965, 30224644). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Revvity Omics, Revvity	RCV003137828	SCV003809655	likely pathogenic	not provided	2022-04-18	criteria provided, single submitter	clinical testing
GeneDx	RCV003137828	SCV003936381	likely pathogenic	not provided	2023-06-21	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: non-functional transactivation and impaired growth suppression ability (Kato et al., 2003; Jordan et al., 2010; Kotler et al., 2018; Giacomelli et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with colorectal cancer, as well as an individual with breast and ovarian cancer who also harbored a BRCA1 variant (Yurgelun et al., 2017; Lerner-Ellis et al., 2021); This variant is associated with the following publications: (PMID: 9546439, 9635858, 9359923, 20407015, 26619011, 30840781, 15161705, 14559903, 12826609, 11793474, 30720243, 15510160, 30224644, 31105275, 32885271, 28135145, 29979965)
Baylor Genetics	RCV003475037	SCV004204272	likely pathogenic	Adrenocortical carcinoma, hereditary	2022-09-30	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004020697	SCV004932639	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-16	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [29979965]. This variant is expected to disrupt protein structure [Myriad internal data].
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355898	SCV001550915	likely pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The TP53 p.Asn239Asp variant was identified in 2 of 474 proband chromosomes (frequency: 0.004) from individuals or families with myelodysplastic syndrome or lung cancer (Belickova 2016, Fouquet 2004). The variant was also identified in dbSNP (ID: rs876660807) as "With Likely pathogenic allele", ClinVar (classified as likely pathogenic by Ambry Genetics and as uncertain significance by Invitae). The variant was not identified in LOVD 3.0 or UMD-LSDB. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The p.Asn239 residue is conserved across mammals and other organisms, and four out of four computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Functional assays in yeast showed that this variant eliminates the transactivation activity of p53 (Flaman 1998; Jordan 2010). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.