Submissions for variant NM_000546.6(TP53):c.604C>T (p.Arg202Cys)

gnomAD frequency: 0.00001  dbSNP: rs587780072

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115729	SCV000149638	uncertain significance	not provided	2020-12-01	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate no damaging effect: functional transactivation and retained growth suppression activity (Kato 2003, Kotler 2018); Observed in an individual with a personal and family history of adrenocortical carcinoma who also harbored a second TP53 missense variant as well as in an individual with HER2-positive lobular breast carcinoma (Herrmann 2012, Gallardo-Alvarado 2019); This variant is associated with the following publications: (PMID: 22170717, 27101868, 22493262, 27146902, 29979965, 30709381, 12826609, 30851333, 28861920, 30840781, 30352134)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000473040	SCV000545281	uncertain significance	Li-Fraumeni syndrome	2024-01-31	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 202 of the TP53 protein (p.Arg202Cys). This variant is present in population databases (rs587780072, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer, adrenocortical carcinoma and acute lymphoblastic leukemia (PMID: 22170717, 29300620, 30709381). ClinVar contains an entry for this variant (Variation ID: 127818). 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, 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.
Ambry Genetics	RCV000563913	SCV000664385	likely benign	Hereditary cancer-predisposing syndrome	2018-10-31	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.
Color Diagnostics, LLC DBA Color Health	RCV000563913	SCV000908790	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-29	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 202 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Experimental studies have reported this variant to be functional in transcriptional transactivation, cell growth suppression and cell proliferation assays (PMID: 12826609, 29979965, 30224644). This variant has been reported in individuals affected with breast cancer, adrenocortical carcinoma, and rectal neuroendocrine tumors in the literature (PMID: 22170717, 30709381, 30851333, 33471991). This variant has been identified in 8/282862 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.
Division of Medical Genetics, University of Washington	RCV001257499	SCV001434317	uncertain significance	Li-Fraumeni syndrome 1	2020-05-05	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in an individual with adrenocortical carcinoma who had a second TP53 variant in cis (Herrmann 2012). This variant has an overall allele frequency of 0.000025 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate that this variant may not alter protein structure/function. Thus, it is unknown at this time whether this variant increases cancer risk. BP4
Sema4, Sema4	RCV000563913	SCV002530471	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-16	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV000115729	SCV003827833	uncertain significance	not provided	2022-06-10	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000115729	SCV004221367	uncertain significance	not provided	2022-08-30	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00017 (6/35440 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with Li-Fraumeni Syndrome (PMID: 28861920 (2017)), acute lymphoblastic leukemia (ALL) (PMID: 29300620 (2018)), and adrenocortical cancer (ACC) (PMID: 22170717 (2012)). Additionally, the variant has been reported both in individuals with breast cancer as well as unaffected individuals in a large breast cancer screening study (PMIDs: 30709381 (2019) and 33471991 (2021), see also LOVD ( https://databases.lovd.nl/shared/variants/TP53). The variant resides within a region known to be important to normal gene function (PMID: 8023157 (1994)) however, there are conflicting reports as to whether the variant itself impacts function (PMIDs: 12826609 (2003), 29979965 (2018), and 30224644 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV000473040	SCV004823780	uncertain significance	Li-Fraumeni syndrome	2023-06-15	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 202 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Experimental studies have reported this variant to be functional in transcriptional transactivation, cell growth suppression and cell proliferation assays (PMID: 12826609, 29979965, 30224644). This variant has been reported in individuals affected with breast cancer, adrenocortical carcinoma, and rectal neuroendocrine tumors in the literature (PMID: 22170717, 30709381, 30851333, 33471991). This variant has been identified in 8/282862 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.
Baylor Genetics	RCV004567015	SCV005054340	uncertain significance	Adrenocortical carcinoma, hereditary	2024-01-29	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000115729	SCV005198837	uncertain significance	not provided	2022-05-27	criteria provided, single submitter	clinical testing