Submissions for variant NM_000546.6(TP53):c.145G>A (p.Asp49Asn)

gnomAD frequency: 0.00001  dbSNP: rs587780728

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000540357	SCV001142537	benign	Li-Fraumeni syndrome	2024-08-05	reviewed by expert panel	curation	The NM_000546.6 :c.145G>A variant in TP53 is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 49 (p.Asp49Asn). This variant has been observed in at least 8 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2; ClinVar SCV: SCV000216702.6). This variant has an allele frequency of 0.0000111525 (18/1613988 alleles) across gnomAD v4.1.0 (after removing low AB alleles likely to represent CHIP contamination and recalculating total allele frequency) which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.232; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing (BP4_Moderate). In summary, this variant meets the criteria to be classified as Benign for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2, PM2_Supporting, BS3, BP4_Moderate. (Bayesian Points: -9; VCEP specifications version 2.0; 7/24/2024)
Ambry Genetics	RCV000165946	SCV000216702	likely benign	Hereditary cancer-predisposing syndrome	2018-09-14	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000423399	SCV000522214	likely benign	not specified	2017-02-28	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000540357	SCV000629784	uncertain significance	Li-Fraumeni syndrome	2025-01-29	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 49 of the TP53 protein (p.Asp49Asn). This variant is present in population databases (rs587780728, gnomAD 0.01%). This missense change has been observed in individual(s) with mesothelioma and skin cancer (PMID: 26554828). ClinVar contains an entry for this variant (Variation ID: 186363). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000423399	SCV000697431	likely benign	not specified	2024-09-23	criteria provided, single submitter	clinical testing	Variant summary: TP53 c.145G>A (p.Asp49Asn) results in a conservative amino acid change located in the Cellular tumor antigen p53, transactivation domain 2 (IPR040926) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 1613988 control chromosomes, predominantly at a frequency of 4.5e-05 within the East Asian subpopulation in the gnomAD database. c.145G>A has been reported in the literature in individuals affected with skin cancer or considered at high risk of breast cancer without strong evidence of causality (e.g. De Rienzo_2016, Su_2021). These reports do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. Publications report experimental evidence evaluating an impact on protein function (e.g. Kato_2003, Leroy_2014, Giacomelli_2018). These results showed no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 24665023, 30224644, 26554828, 23525797, 12826609, 22797305, 34917121). ClinVar contains an entry for this variant (Variation ID: 186363), and a ClinGen expert panel has classified the variant as benign. Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000165946	SCV000905041	likely benign	Hereditary cancer-predisposing syndrome	2020-05-20	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001123209	SCV001282024	uncertain significance	Li-Fraumeni syndrome 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
All of Us Research Program, National Institutes of Health	RCV000540357	SCV004823846	likely benign	Li-Fraumeni syndrome	2024-02-05	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000165946	SCV005415617	benign	Hereditary cancer-predisposing syndrome	2024-11-12	criteria provided, single submitter	clinical testing	The missense variant NM_000546.6(TP53):c.145G>A (p.Asp49Asn) has been reported to ClinVar as Benign with a status of (3 stars) reviewed by expert panel (Variation ID 186363 as of 2024-10-03). There is a small physicochemical difference between aspartic acid and asparagine, which is not likely to impact secondary protein structure as these residues share similar properties. The p.Asp49Asn variant is not predicted to introduce a novel splice site by any splice site algorithm. The p.Asp49Asn missense variant is predicted to be tolerated by both SIFT or PolyPhen2. The asparagine residue at codon 49 of TP53 is present in Chinese hamster and 1 other mammalian species. The nucleotide c.145 in TP53 is not conserved according to a GERP++ and PhyloP analysis of 100 vertebrates. For these reasons, this variant has been classified as Likely Benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004998339	SCV005625950	uncertain significance	not provided	2024-04-12	criteria provided, single submitter	clinical testing	The TP53 c.145G>A (p.Asp49Asn) variant has been reported in the published literature in individuals with different types of cancer including mesothelioma and skin cancer (PMID: 26554828 (2016)), chronic lymphocytic leukemia (PMID: 23525797 (2013)), pediatric brain tumors (PMDI: 22797305 (2012)), and breast cancer (PMID: 34917121 (2021)). Experimental studies have indicated that this variant retains TP53 function (PMIDs: 12826609 (2013), 30224644 (2018), and 34793697 (2021)). The frequency of this variant in the general population, 0.000008 (2/251366 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.