rs587780072
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4BS2
The NM_000546.6(TP53):c.604C>T(p.Arg202Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000958 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000546.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152136Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251480Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135910
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461892Hom.: 0 Cov.: 35 AF XY: 0.00000963 AC XY: 7AN XY: 727248
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Uncertain:4
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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) -
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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. -
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
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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. -
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. -
Li-Fraumeni syndrome Uncertain:2
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). Invitae Evidence Modeling incorporating data from in vitro 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. -
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. -
Li-Fraumeni syndrome 1 Uncertain:1
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 -
Adrenocortical carcinoma, hereditary Uncertain:1
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Choroid plexus papilloma;C0346153:Familial cancer of breast;C0346629:Colorectal cancer;C0585442:Bone osteosarcoma;C1835398:Li-Fraumeni syndrome 1;C1859972:Adrenocortical carcinoma, hereditary;C2239176:Hepatocellular carcinoma;C2750850:Glioma susceptibility 1;C2931038:Familial pancreatic carcinoma;C2931822:Nasopharyngeal carcinoma;C3553606:Basal cell carcinoma, susceptibility to, 7;C4748488:Bone marrow failure syndrome 5 Uncertain:1
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TP53-related disorder Uncertain:1
The TP53 c.604C>T variant is predicted to result in the amino acid substitution p.Arg202Cys. This variant was reported in an individual with adrenocortical carcinoma (Herrmann et al 2012. PubMed ID: 22170717), in an individual with a neuroendocrine tumor (Young Park et al 2019. PubMed ID: 30851333), and in an individual with breast cancer (Gallardo-Alvarado LN et al 2019. PubMed ID: 30709381). This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD. This variant has been classified as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127818/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at