Total submissions: 10
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000166045 | SCV000216806 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-02-23 | criteria provided, single submitter | clinical testing | The p.C176Y pathogenic mutation (also known as c.527G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 527. The cysteine at codon 176 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration is located in the highly conserved domain IV of the DNA binding domain, and is one of four residues necessary to bind the zinc molecule that stabilizes the beta sheet structure of the protein (Martin AC et al. Hum Mutat. 2002 Feb;19(2):149-64). Multiple yeast-based functional studies have demonstrated a loss of transactivation capability for this variant (Epstein CB et al. Oncogene 1998 Apr;16(16):2115-22; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Hassan NM et al. Cancer Lett. 2008 Oct; 270(1):108-19). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Kotler E et al. Mol. Cell 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration has been detected in at least one individual with classic Li-Fraumeni syndrome (LFS) tested by our laboratory (Ambry internal data), and was reported as a de novo alteration in an individual diagnosed with adrenocortical carcinoma at age 5 (Renaux-Petel M et al. J. Med. Genet. 2018 03;55(3):173-180). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
Gene |
RCV000255616 | SCV000322087 | pathogenic | not provided | 2024-12-30 | criteria provided, single submitter | clinical testing | 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; This variant is associated with the following publications: (PMID: 23863845, 15280671, 20516128, 23967324, 25232094, 18555592, 12726864, 9572492, 12509970, 10519380, 26585234, 26552420, 30720243, 31105275, 30840781, 30224644, 29070607, 15510160, 29979965, 12826609, 34273903, 32885271) |
Labcorp Genetics |
RCV000461158 | SCV000545328 | pathogenic | Li-Fraumeni syndrome | 2024-01-03 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 176 of the TP53 protein (p.Cys176Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with adrenocortical carcinoma (PMID: 29070607). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 186451). Advanced modeling performed at Invitae incorporating data from internal and/or published 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 affects TP53 function (PMID: 9572492, 12826609, 29979965, 30224644). For these reasons, this variant has been classified as Pathogenic. |
Genome- |
RCV000166045 | SCV002582492 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-06-18 | criteria provided, single submitter | clinical testing | |
Genome- |
RCV002288754 | SCV002583152 | pathogenic | Li-Fraumeni syndrome 1 | 2022-06-18 | criteria provided, single submitter | clinical testing | |
Liquid Biopsy and Cancer Interception Group, |
RCV003128588 | SCV003806309 | pathogenic | Squamous cell carcinoma | 2022-06-06 | criteria provided, single submitter | research | |
Prevention |
RCV003407616 | SCV004111842 | pathogenic | TP53-related disorder | 2023-02-20 | criteria provided, single submitter | clinical testing | The TP53 c.527G>A variant is predicted to result in the amino acid substitution p.Cys176Tyr. This variant was reported in a patient with adrenocortical carcinoma (Patient F279 in Renaux-Petel et al 2018. PubMed ID: 29070607) and in a patient with ovarian and breast cancer (Supplemental Table, Lerner-Ellis. 2020. PubMed ID: 32885271). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This has been interpreted as likely pathogenic or pathogenic by several submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/186451/). Of note, other variants impacting the same amino acid residue (p.Cys176Ser, p.Cys176Arg, p.Cys176Phe), have also been reported in patients with TP53-related disorders (Table S10 in Maxwell et al. 2016. PubMed ID: 27153395; Whitworth et al. 2016. PubMed ID: 26659639; Human Gene Mutation Database). Based on this evidence, we interpret the c.527G>A (p.Cys176Tyr) variant as pathogenic. |
Baylor Genetics | RCV003474872 | SCV004204270 | pathogenic | Adrenocortical carcinoma, hereditary | 2022-10-13 | criteria provided, single submitter | clinical testing | |
Department of Pathology and Laboratory Medicine, |
RCV001354219 | SCV001548776 | uncertain significance | Familial ovarian cancer | no assertion criteria provided | clinical testing | The TP53 p.Cys176Tyr variant was identified in dbSNP (ID: rs786202962 as “With Likely pathogenic allele”), ClinVar (classified as likely pathogenic by Ambry Genetics and GeneDx and as uncertain significance by Invitae), Cosmic (identified 111x in large intestine, oesophagus, lung, liver, hematopoietic and lymphoid tissue and predicted to be pathogenic), and in Database of germline p53 mutations. The variant was not identified in GeneInsight-COGR, LOVD 3.0, IARC TP53 Database, or UMD TP53 Mutation databases, nor was it identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The variant is located in a zinc-binding site within the DNA-binding domain (Pan 2017, Kato 2003, Kang 2013). Assays of the transactivation activity, mRNA expression, and activity of the mutant p53 provide inconsistent data (Epstein 1998, Kang 2013, Mullany 2015). The p.Cys176 residue is conserved across mammals and other organisms, and 5 of 5 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 5 of 5 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. | |
Key Laboratory of Carcinogenesis and Cancer Invasion, |
RCV003995473 | SCV004046827 | likely pathogenic | Adrenal cortex carcinoma | no assertion criteria provided | clinical testing |