Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV001250514 | SCV001481785 | uncertain significance | Li-Fraumeni syndrome 1 | 2022-03-14 | reviewed by expert panel | curation | This variant has been reported in 1 family meeting Classic LFS criteria (PS4_Supporting; internal clinical contributors). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There are 2 TP53 pathogenic/likely pathogenic variants (p.Y163C, p.A161D) previously reported at this codon (PM5; ClinVar ID 127814, 422295). While rule codes specify application of PM5 code only for those variants found to be Pathogenic, expert opinion in this case allowed for application of PM5 at moderate weight despite one residue's classification as likely pathogenic. This variant was found to co-segregate with disease in multiple affected family members, with 4 meioses observed (PP1_Moderate; internal laboratory contributors). In summary, the clinical significance of TP53 c.482_487del (p.Ala161_Tyr163delinsAsp) is uncertain for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PS4_Supporting, PM2_Supporting, PM5, PP1. |
Johns Hopkins Genomics, |
RCV001250514 | SCV001425306 | likely pathogenic | Li-Fraumeni syndrome 1 | 2020-03-06 | criteria provided, single submitter | clinical testing | |
Invitae | RCV001361575 | SCV001557553 | pathogenic | Li-Fraumeni syndrome | 2023-07-14 | criteria provided, single submitter | clinical testing | This variant, c.482_487del, is a complex sequence change that results in the deletion of 3 and insertion of 1 amino acid(s) in the TP53 protein (p.Ala161_Tyr163delinsAsp). This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 973858). This variant disrupts a region of the TP53 protein in which other variant(s) (p.Ala161Thr) have been determined to be pathogenic (PMID: 29456621; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |