Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000541487 | SCV006279849 | pathogenic | Li-Fraumeni syndrome | 2025-06-05 | reviewed by expert panel | curation | The NM_000546.6: c.490A>G variant in TP53 is a missense variant predicted to cause substitution of lysine by glutamic acid at amino acid 164 (p.Lys164Glu). This variant has been reported in 2 unrelated families meeting Classic/Revised Chompret criteria. Based on this evidence this variant scores 2 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points. (PS4_Moderate; PMIDs: 33138793, 38050059). The variant has been reported to segregate with LFS-associated cancers in 3-4 meioses in 1 family (PP1; PMID: 38050059). At least one individual with this variant was found to have a variant allele fraction of 5-35%, which is a significant predictor of variant pathogenicity (PP4, PMID: 34906512, Internal lab contributors). This variant has an allele frequency of 6.195e-7 (1/1614174 alleles) across gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00003) for PM2_Supporting and has no more than one allele per non-bottleneck subpopulation (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). Computational predictor scores (BayesDel = 0.5572; Align GVGD = Class C55) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). This variant has 9 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (2-9 somatic occurrences, PMID: 30311369) (PM1_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Moderate, PP1, PM2_Supporting, PS3, PP3, PP4, PM1_Supporting. (Bayesian Points: 11; VCEP specifications version 2.3) |
| Myriad Genetics, |
RCV002288937 | SCV004931675 | pathogenic | Li-Fraumeni syndrome 1 | 2024-01-16 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 38050059, 33138793]. |
| Genome- |
RCV002288937 | SCV002582634 | uncertain significance | Li-Fraumeni syndrome 1 | 2022-06-18 | criteria provided, single submitter | clinical testing | |
| Genome- |
RCV002288938 | SCV002582071 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-06-18 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000541487 | SCV000629830 | likely pathogenic | Li-Fraumeni syndrome | 2025-10-09 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 164 of the TP53 protein (p.Lys164Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 32817165, 33138793, 38050059). ClinVar contains an entry for this variant (Variation ID: 246416). 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 affects TP53 function (PMID: 12826609, 29979965, 30224644). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Gene |
RCV000235745 | SCV000293963 | uncertain significance | not provided | 2017-12-27 | criteria provided, single submitter | clinical testing | This variant is denoted TP53 c.490A>G at the cDNA level, p.Lys164Glu (K164E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAG>GAG). This variant has not, to our knowledge, been published in the literature as either a pathogenic germline variant or a benign polymorphism. However, it has been reported as a somatic variant in multiple tumor types including breast, ovarian, liver, head and neck, and leukemia (Lunn1997, Wang 2004, Pekova 2011, Van der Vorst 2012, Saal 2015). A yeast functional study using a head and neck tumor carrying this variant demonstrated deficient transciptional activity, however this tumor also carried another TP53 variant (Van der Vorst 2012). TP53 Lys164Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Lysine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Lys164Glu occurs at a position that is conserved across species and is located in the DNA-binding domain (Bode 2004). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether TP53 Lys164Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |