ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs587780728
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen RCV000540357 SCV001142537 likely benign Li-Fraumeni syndrome 2019-08-28 reviewed by expert panel curation This variant has a BayesDel score < 0.16 and Align GVGD (Zebrafish) is Class C0 or Class C15 (BP4). Additionally, transactivation assays show retained function 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; PMID: 12826609, 30224644). In summary, TP53 c.145G>A; p.Asp49Asn meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BP4 and BS3.
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.
Invitae RCV000540357 SCV000629784 uncertain significance Li-Fraumeni syndrome 2023-12-08 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). Advanced modeling performed at Invitae incorporating data from internal and/or published 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 RCV000589340 SCV000697431 uncertain significance not provided 2016-04-25 criteria provided, single submitter clinical testing Variant summary: The TP53 c.145G>A variant affects a non-conserved nucleotide, resulting in an amino acid change from a medium size and acidic Asp to a medium size and polar Asn. 4/5 in-silico tools predict this variant to be benign. Functional studies have shown that this variant has ~50% transcriptional activity of wild type protein, but it is unknown if this decrease in activity is physiologically relevant to the test phenotype. This variant was found in 1/121058 control chromosomes at a frequency of 0.0000083, which does not exceed maximal expected frequency of a pathogenic TP53 allele (0.0000354). The variant has been identified in at least 1 skin cancer patient without significant evidence of causality (i.e. co-segregation data). At least one clinical lab has classified this variant as likely benign without providing evidence to independently evaluate. Taken together, this variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
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

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