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

dbSNP: rs2073376974

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV001361575	SCV001481785	likely pathogenic	Li-Fraumeni syndrome	2024-09-06	reviewed by expert panel	curation	The NM_000546.6:c.482_487del variant is predicted to cause a change in the length of the protein (p.Ala161_Tyr163delinsAsp) due to an in-frame deletion of 3 amino acids and insertion of 1 amino acid. This variant has been reported in 1 family meeting Classic Li-Fraumeni syndrome criteria. Based on this evidence, this variant scores 1 total points meeting the TP53 VCEP phenotype scoring criteria of 1-1.5 points. (PS4_Supporting; Internal contributors). The variant has been reported to segregate with LFS-associated cancers in 3-4 meioses in 1 family (PP1; Internal contributors). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The individual missense variants, A161D and Y163D, used as proxies for this indel variant have 7 and 3 somatic occurrences, respectively, 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). Another missense variant (c.488A>G, p.Tyr163Cys) (ClinVar Variation ID: 127814), in an involved codon has been classified as pathogenic for Li-Fraumeni syndrome by the ClinGen TP53 VCEP’s specifications (PM5). In summary, this variant meets the criteria to be classified as Likely Pathogenic for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Supporting, PP1, PM2_Supporting, PM1_Supporting, PM5. (Bayesian Points: 6; VCEP specifications version 2.0; 9/6/2024)
Johns Hopkins Genomics, Johns Hopkins University	RCV001250514	SCV001425306	likely pathogenic	Li-Fraumeni syndrome 1	2020-03-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001361575	SCV001557553	pathogenic	Li-Fraumeni syndrome	2023-07-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 973858). This variant has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (Invitae). This variant is not present in population databases (gnomAD no frequency). 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).
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].