rs587780068
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PP3_StrongPP5BS2
The NM_001276697.3(TP53):c.-6C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,614,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001276697.3 5_prime_UTR_premature_start_codon_gain
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251276Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135854
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461886Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2AN XY: 727246
GnomAD4 genome 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74346
ClinVar
Submissions by phenotype
not provided Pathogenic:2Uncertain:2
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer, glioblastoma, sarcoma, or adult-onset adrenocortical and testicular cancers (PMID: 22170717, 28724667, 29958926, 29625052, 33051313, 31119730, 33471991, 32817165, 37623222); Published functional studies demonstrate partially functional transactivation and no impact on growth suppression, while others suggest a possible dominant-negative effect and reduced p53 functionality in patient cells (PMID: 10519380, 12826609, 12917626, 30224644, 29979965, 33051313); This variant is associated with the following publications: (PMID: 7700647, 25634010, 29625052, 30224644, 30840781, 22170717, 14559903, 17947339, 23200980, 24908601, 23531339, 25234657, 29979965, 28861920, 28724667, 12917626, 12826609, 30352134, 29958926, 15906354, 24326041, 10519380, 12909720, 30089713, 30128536, 30720243, 31105275, 33051313, 31119730, 29922827, 32817165, 30130155, 15510160, 38702830, 37319387, 36451132, EaV2024[casereport], 33471991, 35820297, 34273903, 37623222, 38332006, 38892462, 39179735) -
The TP53 p.Arg158Cys variant was identified in 1 of 206 proband chromosomes (frequency: 0.005) from an individual with adrenocortical cancer and testicular cancer (Herrmann 2011). The variant was also identified in the following databases: dbSNP (ID: rs587780068) as "With Likely pathogenic allele ", ClinVar (2x uncertain significance, 2x likely pathogenic), Clinvitae (3x uncertain significance), Cosmic (23x, confirmed somatic, in cancer of the large intestine, urinary tract, lung, endometrium, haematopoietic, and lymphoid system), IARC TP53 Database (21x somatic, partially functional transcriptional activity), and the UMD TP52 Mutation Database. The variant was not identified in GeneInsight-COGR, LOVD 3.0, or the Database of Germline p53 Mutations. The variant was identified in control databases in 2 of 246112 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European in 2 of 111580 chromosomes (freq: 0.00002), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. In vitro yeast based functional assays have demonstrated this variant inhibits transactivation and is temperature sensitive (Monti 2003, Shiraishi 2004). Different missense substitutions at this codon have been determined to be pathogenic (Ruijis 2009, Wasserman 2015). The p.Arg158 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
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Li-Fraumeni syndrome Uncertain:3
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 158 of the TP53 protein (p.Arg158Cys). This variant is present in population databases (rs587780068, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 22170717, 28724667, 29625052, 31105275, 32817165). ClinVar contains an entry for this variant (Variation ID: 127812). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 12917626, 14559903, 29979965). 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. -
Data included in classification: UK family 1: Proband ACC at 11. Unaffected mother carries variant, maternal great uncle possible brain tumour and another maternal great-uncle in died in 20s (meets Chompret criteria). Literature/IARC case 1: ACC at 39 and testicular ca at 20. Herrmann et al, 2012 (PMID: 22170717, IARC ref 261) (meets Chompret criteria) (PS4_sup). The variants p.Arg158His and p.Arg158Leu at the same codon are considered likely pathogenic/pathogenic (PM5_mod). Variant is class 65 on AlignGVGD and Bayes del score 0.51 (PP3_mod). Data not included in classification: Variant observed in 2/125,638 gnomAD controls. Multiple reports of variant on IARC database with limited clinical information. Literature/IARC family 2: Proband breast cancer age 49 (Er+ve, PR +ve, Her2 -ve), fibrosarcoma at 59 in FDR, breast cancer at 50 in SDR, Lung cancer at 70 in SDR, cancer of unknown primary at 47 in SDR (Meiss et al. 2018, PMID: 29958926, IARC Ref 422). Kato et al. 2003 (PMID 12826609): Transactivation class partially functional, Giacomelli et al. 2018 (PMID 30224644) Combined model score: 123.6556. IARC classification: unclassified. -
This missense variant replaces arginine with cysteine at codon 158 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown that the mutant protein is partially functional in yeast transactivation assays (IARC database and PMID: 12826609) and functional in human cell proliferation assay (PMID: 29979965). The variant impact on function was inconclusive in human cell growth suppression assays (PMID: 30224644). This variant has been reported in an individual affected with cutaneous carcinosarcoma who also harbored apathogenic co-variant (TP53 p.Arg273Pro; PMID: 33089535), in an individual affected with adrenocortical carcinoma with a family history of leukemia, lung cancer and adrenocortical carcinoma (PMID: 22170717); in an individual affected with breast cancer with a family history of fibrosarcoma, breast cancer and lung cancer (PMID: 29958926); and in at least two other individuals affected with breast cancer (PMID: 31119730, 33471991, 35820297). This variant has also been observed in individuals affected with pancreatic cancer and colorectal cancer (PMID: 23200980, 29844874). This variant has been identified in 2/251276 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant at the same position, p.Arg158His, is known to be pathogenic (Clinvar variation ID: 141963). 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. -
Hereditary cancer-predisposing syndrome Uncertain:2
The p.R158C variant (also known as c.472C>T), located in coding exon 4 of the TP53 gene, results from a C to T substitution at nucleotide position 472. The arginine at codon 158 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was reported in the literature as being found in a patient diagnosed with adrenocortical carcinoma and secondary testicular cancer (Herrmann LJ et al. J. Clin. Endocrinol. Metab. 2012 Mar;97(3):E476-85), in several individuals with breast cancer (Sun J. et al. Clin Cancer Res. 2017 Oct;23(20):6113-6119; Meiss AE. et al. Hum Pathol. 2018 12;82:20-31), in a patient with glioblastoma (Huang KL. et al. Cell. 2018 04;173(2):355-370.e14), and in a patient with leiomyosarcoma (Raad S. et al. J Med Genet. 2021 12;58(12):796-805). This variant is in the DNA binding domain of the TP53 protein and is reported to have partially functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is proficient at growth suppression, but has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
This missense variant replaces arginine with cysteine at codon 158 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown that the mutant protein is partially functional in yeast transactivation assays (IARC database and PMID: 12826609) and functional in human cell proliferation assay (PMID: 29979965). The variant impact on function was inconclusive in human cell growth suppression assays (PMID: 30224644). This variant has been reported in an individual affected with cutaneous carcinosarcoma who also harbored apathogenic co-variant (TP53 p.Arg273Pro; PMID: 33089535), in an individual affected with adrenocortical carcinoma with a family history of leukemia, lung cancer and adrenocortical carcinoma (PMID: 22170717); in an individual affected with breast cancer with a family history of fibrosarcoma, breast cancer and lung cancer (PMID: 29958926); and in at least two other individuals affected with breast cancer (PMID: 31119730, 33471991, 35820297). This variant has also been observed in individuals affected with pancreatic cancer and colorectal cancer (PMID: 23200980, 29844874). This variant has been identified in 2/251276 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant at the same position, p.Arg158His, is known to be pathogenic (Clinvar variation ID: 141963). 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. -
Lip and oral cavity carcinoma Pathogenic:1
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not specified Uncertain:1
Variant summary: TP53 c.472C>T (p.Arg158Cys) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251276 control chromosomes. c.472C>T has been reported in the literature in individuals affected with Li-Fraumeni Syndrome (Herrmann_2012, Rana_2019), Breast Cancer (Sun_2017) and Glioblastoma (Huang_2018). A different variant affecting the same codon has been classified as pathogenic by our lab (c.473G>A, p.Arg158Gly), supporting the critical relevance of codon 158 to TP53 protein function. Several publications report experimental evidence evaluating an impact on protein function. Studies indicate this variant results in growth suppression but has a dominant negative effect (Kotler_2018, Giacomelli_2018), also shows partially functional transactiviation in yeast based assays (Kato_2003), partial loss of function (Monti_2003) and associated with changes in temperature sensitivity (Shiraishi_2004). The following publications have been ascertained in the context of this evaluation (PMID: 30224644, 22170717, 29625052, 12826609, 12917626, 31105275, 14559903, 28724667, 29979965). ClinVar contains an entry for this variant (Variation ID: 127812). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
Li-Fraumeni syndrome 1 Uncertain:1
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Hereditary breast ovarian cancer syndrome Uncertain:1
PM1, PP3, PS4_sup. According to the ClinGen ACMG TP53 v1.4.0 criteria we chose these criteria: PS4 (supporting pathogenic): Identified in multiple families fullfilling chompret criteria see ClinVar, PM1 (medium pathogenic): # of IARC somatic mutations (human tumors) 21; 5 somatic observations cancerhotspots.org, PP3 (medium pathogenic): BayesDel noAF noAF score 0.5145, Substitution GV GD PredictionR158C 0.00 179.53 Class C65, BS3 (supporting benign): Transactivation assays in yeast (IARC classification based on data from Kato et al, 2003) that demonstrate a partially functioning allele (>20% and <=75% activity) AND: No evidence of DNE + no evidence of LOF from Giacomelli, et al data. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at