ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.14A>G (p.Gln5Arg)

gnomAD frequency: 0.00001  dbSNP: rs781595324
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000220312 SCV000277587 likely benign Hereditary cancer-predisposing syndrome 2021-03-16 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000550564 SCV000629785 uncertain significance Li-Fraumeni syndrome 2024-05-16 criteria provided, single submitter clinical testing This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 5 of the TP53 protein (p.Gln5Arg). This variant is present in population databases (rs781595324, gnomAD 0.003%). 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: 233248). 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). 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.
Color Diagnostics, LLC DBA Color Health RCV000220312 SCV000691582 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-12 criteria provided, single submitter clinical testing This missense variant replaces glutamine with arginine at codon 5 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). Functional studies have shown that this variant does not adversely impact TP53 protein function (PMID: PMID: 12826609, 30224644). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/250676 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.
GeneDx RCV001575870 SCV001802952 uncertain significance not provided 2019-05-08 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30224644, 28861920, 30886117)
Genome-Nilou Lab RCV000220312 SCV002582187 uncertain significance Hereditary cancer-predisposing syndrome 2022-06-18 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002288887 SCV002582750 uncertain significance Li-Fraumeni syndrome 1 2022-06-18 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV000550564 SCV004823870 uncertain significance Li-Fraumeni syndrome 2023-06-08 criteria provided, single submitter clinical testing This missense variant replaces glutamine with arginine at codon 5 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). Functional studies have shown that this variant does not adversely impact TP53 protein function (PMID: PMID: 12826609, 30224644). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/250676 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.

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