17-7675075-A-T

Position:

• chr17-7675075-A-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS2_Moderate PM1 PM2_Supporting PS3 PS1_Moderate PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.537T>A variant in TP53 is a missense variant predicted to cause substitution of histidine by glutamine at amino acid 179 (p.His179Gln). 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). This variant has 12 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 (≥ 10 somatic occurrences, PMID:30311369). The same amino acid change (p.His179Gln), resulting from a different nucleotide change (c.537T>G) (ClinVar Variation ID: 376607; PMIDs: 18511570, 31119730), is classified as likely pathogenic for Li-Fraumeni syndrome by following the ClinGen TP53 VCEP’s specifications. Splicing prediction using SpliceAI revealed no expected impact on splicing due to either variant (PS1_Moderate). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with an LFS-associated cancer totaling 2 phenotype points (PS2_Moderate; PMID:19556618). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID:34906512, Internal lab contributor: SCV000664423.4). 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: PS3, PM1, PS1_Moderate, PS2_Moderate, PP4_Moderate, PM2_Supporting. (Bayesian Points: 13; VCEP specifications version 2.0; 7/24/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA16615708/MONDO:0018875/009

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: -0.556

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]

TP53 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.537T>A	p.His179Gln	missense_variant	5/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.537T>A	p.His179Gln	missense_variant	5/11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461884 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Li-Fraumeni syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 24, 2022	This missense change has been observed in individual(s) with Li-Fraumeni syndrome and follicular lymphoma (PMID: 18628487, 19556618). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 16209708, 17311302, 22540896, 29979965, 30224644). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. ClinVar contains an entry for this variant (Variation ID: 406578). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 179 of the TP53 protein (p.His179Gln). -
Pathogenic, reviewed by expert panel	curation	ClinGen TP53 Variant Curation Expert Panel, ClinGen	Aug 05, 2024	The NM_000546.6: c.537T>A variant in TP53 is a missense variant predicted to cause substitution of histidine by glutamine at amino acid 179 (p.His179Gln). 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). This variant has 12 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 (≥ 10 somatic occurrences, PMID: 30311369). The same amino acid change (p.His179Gln), resulting from a different nucleotide change (c.537T>G) (ClinVar Variation ID: 376607; PMIDs: 18511570, 31119730), is classified as likely pathogenic for Li-Fraumeni syndrome by following the ClinGen TP53 VCEP’s specifications. Splicing prediction using SpliceAI revealed no expected impact on splicing due to either variant (PS1_Moderate). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with an LFS-associated cancer totaling 2 phenotype points (PS2_Moderate; PMID: 19556618). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributor: SCV000664423.4). 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: PS3, PM1, PS1_Moderate, PS2_Moderate, PP4_Moderate, PM2_Supporting. (Bayesian Points: 13; VCEP specifications version 2.0; 7/24/2024) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2024

The p.H179Q pathogenic mutation (also known as c.537T>A), located in coding exon 4 of the TP53 gene, results from a T to A substitution at nucleotide position 537. The histidine at codon 179 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in a kindred meeting Chompret crieria for Li-Fraumeni syndrome (LFS) (Gonzalez KD et al. J. Med. Genet. 2009 Oct;46:689-93). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation in yeast based assays (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Kotler E et al. Mol. Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). The amino acid residue altered by this variant has been shown to be functionally important for zinc binding, and alterations affecting this amino acid have been associated with poorer prognosis in breast cancer patients (Martin AC et al. Hum. Mutat. 2002 Feb;19:149-64; Olivier M et al. Clin. Cancer Res. 2006 Feb;12:1157-67). Another amino acid change at this codon (p.H179Y) has been reported as pathogenic in multiple cases and functional studies (Wasserman JD et al. J. Clin. Oncol. 2015 Feb 20;33(6):602-9; Pan Y et al. Nucleic Acids Res. 2014 Oct;42(18):11570-88), and a different alteration leading to this same amino acid substitution p.H179Q (c.537T>G) has been reported in a French family with a clinical history suggestive of Li-Fraumeni syndrome (Bougeard G et al. J. Med. Genet. 2008 Aug;45(8):535-8), and in a woman with breast cancer at age 27 (Sheng S et al. Int. J. Cancer, 2020 01;146:487-495). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Ovarian neoplasm Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

University Health Network, Princess Margaret Cancer Centre

Mar 19, 2021

- -

Acute myeloid leukemia Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Hematological Lab, University of Education

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Benign	2.0
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.88	D;D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.;D
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.82	T;T;T;T;T;D;T;T;.;.;.;T;T;.;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	.;.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-7.7	D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Polyphen		1.0	D;.;.;.;.;.;.;.;.;D;.;D;D;D;.;.;D;.;.;.;D
Vest4		0.90
MutPred		0.95		Gain of helix (P = 0.132);Gain of helix (P = 0.132);.;.;.;.;.;.;.;Gain of helix (P = 0.132);.;Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);.;.;Gain of helix (P = 0.132);.;.;.;.;
MVP		0.98
MPC		1.7
ClinPred		1.0	D
GERP RS		-9.2
Varity_R		0.99
gMVP		0.78

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: rs876660821; hg19: chr17-7578393; COSMIC: COSV52669519; COSMIC: COSV52669519;