ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.466C>T (p.Arg156Cys)

gnomAD frequency: 0.00002  dbSNP: rs563378859
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000213051 SCV000149630 likely benign not provided 2020-09-18 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate retention of growth suppression and apoptotic activities, and partial or wildtype-like transcriptional activation (Kato 2003, Kakudo 2005, Kotler 2018); Observed in individuals with HER2-negative breast cancer (Sun 2017, Sheng 2019); This variant is associated with the following publications: (PMID: 12826609, 15781620, 23200980, 26068095, 28477877, 14559903, 28724667, 29979965, 25348012, 22983585, 28861920, 30871527, 30352134, 30840781, 28251968, 31119730)
Ambry Genetics RCV000115721 SCV000185652 likely benign Hereditary cancer-predisposing syndrome 2022-08-18 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.
Invitae RCV000232885 SCV000285198 uncertain significance Li-Fraumeni syndrome 2024-01-07 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 156 of the TP53 protein (p.Arg156Cys). This variant is present in population databases (rs563378859, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 28724667). ClinVar contains an entry for this variant (Variation ID: 127810). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TP53 protein function with a negative predictive value of 95%. 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.
Counsyl RCV000409094 SCV000488318 uncertain significance Li-Fraumeni syndrome 1 2016-02-25 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000764146 SCV000895131 uncertain significance Adrenocortical carcinoma, hereditary; Familial cancer of breast; Glioma susceptibility 1; Bone osteosarcoma; Li-Fraumeni syndrome 1; Nasopharyngeal carcinoma; Carcinoma of pancreas; Choroid plexus papilloma; Carcinoma of colon; Basal cell carcinoma, susceptibility to, 7; Hepatocellular carcinoma 2018-10-31 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000115721 SCV000911117 likely benign Hereditary cancer-predisposing syndrome 2017-01-27 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000115721 SCV002530460 uncertain significance Hereditary cancer-predisposing syndrome 2021-05-03 criteria provided, single submitter curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV002465516 SCV002760886 uncertain significance not specified 2023-08-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002465516 SCV003800821 uncertain significance not specified 2023-01-03 criteria provided, single submitter clinical testing Variant summary: TP53 c.466C>T (p.Arg156Cys) results in a non-conservative amino acid change located in the p53, DNA-binding domain (IPR011615) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251282 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.466C>T has been reported in the literature in individuals affected with breast cancer (Sun_2017, Sheng_2020, PMID 33471991), but it has also been reported in unaffected controls (PMID 33471991). These report(s) do not provide unequivocal conclusions about association of the variant with disease. The IARC database reports the variant as being partially-functional based on overall transcription activity (TA) on eight different promoters as measured in yeast assays by Kato et al (2003). However, multiple other studies using an array of different assays determined the variant to be functional (Kakudo_2005, Giacomelli_2018, Kotler_2018, Doffe_2021). Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and three ClinVar submitters (evaluation after 2014) cite it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity RCV000213051 SCV003827834 uncertain significance not provided 2021-02-24 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000409094 SCV004017916 uncertain significance Li-Fraumeni syndrome 1 2023-04-12 criteria provided, single submitter clinical testing This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics RCV003467058 SCV004206224 uncertain significance Adrenocortical carcinoma, hereditary 2023-10-05 criteria provided, single submitter clinical testing

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