ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.482_487del (p.Ala161_Tyr163delinsAsp)

dbSNP: rs2073376974
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen 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, Johns Hopkins University 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.
Myriad Genetics, Inc. RCV001250514 SCV004931146 likely pathogenic Li-Fraumeni syndrome 1 2024-02-14 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].

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