rs1555526478

Positions:

• chr17-7675997-G-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS2 PVS1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000546.6 c.372C>A (p.Cys124Ter) is a TP53 nonsense variant upstream of p.Lys351. The variant is predicted to undergo nonsense-mediated decay (PVS1; PMID:22233476). This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 2 individuals with LFS-associated cancers totaling 4 phenotype points (PS2; PMID:22233476, 32658383). This variant is absent from gnomAD v4.1.0 (PM2_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: PVS1, PS2, PM2_Supporting. (Bayesian Points: 13; VCEP specifications version 2.0; 7/24/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA397844214/MONDO:0018875/009

• Frequency: Genomes: not found (cov: 32)
• Consequence: TP53 NM_000546.6 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 0.705

Genes affected

TP53 (HGNC:11998): (tumor protein p53) This gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Mutations in this gene are associated with a variety of human cancers, including hereditary cancers such as Li-Fraumeni syndrome. Alternative splicing of this gene and the use of alternate promoters result in multiple transcript variants and isoforms. Additional isoforms have also been shown to result from the use of alternate translation initiation codons from identical transcript variants (PMIDs: 12032546, 20937277). [provided by RefSeq, Dec 2016]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.372C>A	p.Cys124Ter	stop_gained	4/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.372C>A	p.Cys124Ter	stop_gained	4/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Li-Fraumeni syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 26, 2023	This sequence change creates a premature translational stop signal (p.Cys124*) in the TP53 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TP53 are known to be pathogenic (PMID: 20522432). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with childhood adrenocortical carcinoma (PMID: 22233476). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 458537). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen TP53 Variant Curation Expert Panel, ClinGen	Aug 28, 2019	The p.Cys124* variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There is a de novo observation of a proband with adrenocortical carcinoma in childhood without mention of parental confirmation (PM6; PMID: 22233476). In summary, TP53 c.372C>A; p.Cys124* meets criteria to be classified as pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PVS1, PM2_Supporting, PM6. -

Li-Fraumeni syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Feb 13, 2024

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.88	D
MutationTaster	Benign	1.0	A;A;A;A;A;A
Vest4		0.87
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555526478; hg19: chr17-7579315; COSMIC: COSV52944837; COSMIC: COSV52944837;