ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.717C>G (p.Asn239Lys)

dbSNP: rs1057522275
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000431317 SCV000526938 uncertain significance not provided 2018-03-19 criteria provided, single submitter clinical testing This variant is denoted TP53 c.717C>G at the cDNA level, p.Asn239Lys (N239K) at the protein level, and results in the change of an Asparagine to a Lysine (AAC>AAG). This variant has not, to our knowledge, been published as a germline variant, but has been reported as a somatic variant in oral, renal, and other tumors (Yamakazi 2003, Scott 2012, COSMIC). This variant is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). Additionally, functional studies by Epstein et al. (1998) revealed loss of transactivation as well as a dominant-negative effect. TP53 Asn239Lys was not observed in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Despite some evidence suggesting pathogenicity, based on currently available evidence we consider TP53 Asn239Lys to be a variant of uncertain significance.
Ambry Genetics RCV000492173 SCV000581154 likely pathogenic Hereditary cancer-predisposing syndrome 2023-06-05 criteria provided, single submitter clinical testing The p.N239K variant (also known as c.717C>G) is located in coding exon 6 of the TP53 gene. This alteration results from a C to G substitution at nucleotide position 717. The asparagine at codon 239 is replaced by lysine, an amino acid with very few similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity and is predicted to affect several p53 isoforms (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). Studies conducted in human cell lines are equivocal about this variant's ability to suppress cell growth (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Internal structural analysis predicts this amino acid change will result in a significant decrease in structural stability (Cho Y Science 1994 Jul; 265(5170):346-55). In addition, another alteration at this position, p.N239D, has been shown to impair TP53 protein function and stability (Ambry internal data; Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000529909 SCV000629858 uncertain significance Li-Fraumeni syndrome 2021-09-17 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 239 of the TP53 protein (p.Asn239Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 33245408). ClinVar contains an entry for this variant (Variation ID: 385614). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 protein function (PMID: 12826609, 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.
Baylor Genetics RCV003463830 SCV004206221 likely pathogenic Adrenocortical carcinoma, hereditary 2024-01-25 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000492173 SCV004359988 uncertain significance Hereditary cancer-predisposing syndrome 2023-07-19 criteria provided, single submitter clinical testing This missense variant replaces asparagine with lysine at codon 239 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported this variant to be partially defective in transactivation assays (PMID: 12826609), but inconclusive in human cell growth and proliferation assays (PMID: 29979965, 30224644). This variant has been reported in two individuals affected with either classic or chompret Li Fraumeni syndrome (PMID: 33245408, 34805717). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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