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

gnomAD frequency: 0.00002  dbSNP: rs563378859

Total submissions: 13

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000232885	SCV000285198	uncertain significance	Li-Fraumeni syndrome	2024-11-20	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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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
Fulgent Genetics, Fulgent Genetics	RCV005016392	SCV005651990	uncertain significance	Adrenocortical carcinoma, hereditary; Familial cancer of breast; Glioma susceptibility 1; Bone osteosarcoma; Li-Fraumeni syndrome 1; Nasopharyngeal carcinoma; Choroid plexus papilloma; Basal cell carcinoma, susceptibility to, 7; Familial pancreatic carcinoma; Hepatocellular carcinoma; Colorectal cancer; Bone marrow failure syndrome 5	2024-06-04	criteria provided, single submitter	clinical testing