ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.145G>A (p.Asp49Asn) (rs587780728)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165946 SCV000216702 likely benign Hereditary cancer-predisposing syndrome 2016-11-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other data supporting benign classification
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 2018-07-10 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 49 of the TP53 protein (p.Asp49Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs587780728, ExAC 0.002%). This variant has been reported in an individual affected with mesothelioma and skin cancer (PMID: 26554828). ClinVar contains an entry for this variant (Variation ID: 186363). An experimental study in yeast has shown that this missense change does not affect TP53 transactivation activity (PMID: 12826609). 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.
Integrated Genetics/Laboratory Corporation of America 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 RCV000165946 SCV000905041 benign Hereditary cancer-predisposing syndrome 2016-01-14 criteria provided, single submitter clinical testing

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