Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000467183 | SCV001949912 | likely benign | Li-Fraumeni syndrome | 2025-01-16 | reviewed by expert panel | curation | The NM_000546.6: c.556G>A variant in TP53 is a missense variant predicted to cause substitution of aspartic acid by asparagine at amino acid 186 (p.Asp186Asn). This variant has an allele frequency of 0.00003332 (2/60018 alleles) in the Admixed American population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.0517; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PM2_Supporting, BS3, BP4_Moderate. (Bayesian Points: -5; VCEP specifications version 2.1; 1/16/2025). |
| Labcorp Genetics |
RCV000467183 | SCV000545352 | uncertain significance | Li-Fraumeni syndrome | 2025-01-23 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 186 of the TP53 protein (p.Asp186Asn). This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 406601). 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. |
| Gene |
RCV000481372 | SCV000566478 | likely benign | not provided | 2019-09-10 | criteria provided, single submitter | clinical testing | This variant is associated with the following publications: (PMID: 17903248, 21232794, 29979965, 30224644, 30287823, 17417775, 30840781) |
| Ambry Genetics | RCV000571882 | SCV000664581 | likely benign | Hereditary cancer-predisposing syndrome | 2020-06-11 | 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. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000481372 | SCV002046459 | uncertain significance | not provided | 2020-12-03 | criteria provided, single submitter | clinical testing |