Submissions for variant NM_000546.6(TP53):c.393C>A (p.Asn131Lys)

gnomAD frequency: 0.00001  dbSNP: rs769270327

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000465360	SCV001429627	uncertain significance	Li-Fraumeni syndrome	2020-08-11	reviewed by expert panel	curation	This variant has been reported in 4 probands meeting Chompret criteria (PS4_Moderate; PMID: Internal laboratory contributors, SCV000293984.11, SCV000581099.3, National Cancer Institute). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; Internal laboratory contributor, SCV000545263.5). Transactivation assays show a partially functional variant according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3_Supporting; PMID: 12826609, 30224644). In summary, the clinical significance of TP53 c.393C>A (p.Asn131Lys) is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PS4_Moderate, BS3_Supporting, BS2_Supporting.
GeneDx	RCV000236166	SCV000293984	uncertain significance	not provided	2018-02-27	criteria provided, single submitter	clinical testing	This variant is denoted TP53 c.393C>A at the cDNA level, p.Asn131Lys (N131K) at the protein level, and results in the change of an Asparagine to a Lysine (AAC>AAA). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported in a colorectal tumor, along with another TP53 missense variant, and a myeloid neoplasm (Cleven 2015, Jauhri 2017). This variant is reported as having partially functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Asn131Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). TP53 Asn131Lys is located within the DNA binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether TP53 Asn131Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000465360	SCV000545263	uncertain significance	Li-Fraumeni syndrome	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 131 of the TP53 protein (p.Asn131Lys). This variant is present in population databases (rs769270327, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 246429). 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 with a positive predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 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.
Ambry Genetics	RCV000492741	SCV000581099	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-21	criteria provided, single submitter	clinical testing	The p.N131K variant (also known as c.393C>A), located in coding exon 4 of the TP53 gene, results from a C to A substitution at nucleotide position 393. The asparagine at codon 131 is replaced by lysine, an amino acid with similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have partially 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 proficient at growth suppression and has no 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). While there are no reports of p.N131K as a germline alteration in the literature, another alteration at this same position, p.N131I, was reported in a Li-Fraumeni syndrome family (Agarwalla PK et al. Pediatr Neurosurg. 2008;44(6):501-8). This amino acid position is highly conserved through mammals but not in all available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000492741	SCV000903736	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-08	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with lysine at codon 131 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). An experimental functional studies in yeast demonstrated a partial impact of this variant on TP53 transactivation activity (PMID 12826609), but the variant behaved like wild-type in human cell growth suppression and proliferation assays (PMID: 29979965, 30224644). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/282018 chromosomes 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000236166	SCV002009074	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003463702	SCV004206257	uncertain significance	Adrenocortical carcinoma, hereditary	2024-03-08	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236166	SCV004221355	uncertain significance	not provided	2022-12-15	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00029 (3/10362 chromosomes in Ashkenazi Jewish subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with myeloid neoplasm (PMID: 25412846 (2015)) and breast cancer (PMID: 27713152 (2016)) but has not been confirmed to occur in the germline state in the literature. Functional studies have concluded this variant to be partially functional in transactivation (PMID: 12826609 (2003)) and mostly functional in cell proliferation (PMID: 29979965 (2018)). In addition, the variant did not exhibit loss of function (LOF) or dominant negative effect (DNE) (PMID: 30224644 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV000465360	SCV004823810	uncertain significance	Li-Fraumeni syndrome	2023-05-31	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with lysine at codon 131 of the TP53 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). An experimental functional studies in yeast demonstrated a partial impact of this variant on TP53 transactivation activity (PMID 12826609), but the variant behaved like wild-type in human cell growth suppression and proliferation assays (PMID: 29979965, 30224644). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/282018 chromosomes 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.