17-7673784-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000546.6(TP53):c.836G>A(p.Gly279Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G279R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:2
• Conservation: PhyloP100: 6.16

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 17 uncertain in NM_000546.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant 17-7673784-C-T is Pathogenic according to our data. Variant chr17-7673784-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 419454.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Pathogenic=3, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.836G>A	p.Gly279Glu	missense_variant	8/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.836G>A	p.Gly279Glu	missense_variant	8/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Li-Fraumeni syndrome 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 20, 2024	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 16508005]. This variant is expected to disrupt protein structure [Myriad internal data]. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 07, 2019	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 8633021, 7718482, 9364015, 11429700, 11429705, 11313981, 16508005, 12909720, 12917626, 29979965, 16861262, 11896595, 30166522, 33504652) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2019	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 12, 2022	The p.G279E pathogenic mutation (also known as c.836G>A), located in coding exon 7 of the TP53 gene, results from a G to A substitution at nucleotide position 836. The glycine at codon 279 is replaced by glutamic acid, an amino acid with a few similar properties. This alteration has been detected in individuals meeting classic Li-Fraumeni diagnostic criteria as well as Chompret criteria (Ambry internal data). This alteration is located in the functionally critical DNA-binding domain. A number of functional assays in both yeast and mammalian cells have shown this alteration to be devoid of transactivation activity, deficient in the induction of apoptosis, and unable to suppress cell growth after UV irradiation (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Menendez D et al. Mol. Cell. Biol. 2006 Mar; 26(6):2297-308; Inga A et al. Oncogene. 2001 Jan; 20(4):501-13; Rokudai Set al. J Biol Chem. 2009 Jan 2;284(1):237-44; Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat Genet. 2018 10;50:1381-1387). Additionally, this variant has been shown to exhibit strong dominant-negative characteristics (Dearth LR et al. Carcinogenesis 2007 Feb; 28(2):289-98; Brachmann RK et al. Proc. Natl. Acad. Sci. U.S.A. 1996 Apr; 93(9):4091-5). Structural analysis indicates that G279 is adjacent to several DNA binding residues, and the p.G279E change creates severe structural perturbations (>15 kcal/mol) resulting in a destabilization of the proper folding of the adjacent loop (Ambry internal analysis). 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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -

Neoplasm of ovary Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Dec 01, 2018

- -

Squamous cell carcinoma of the head and neck Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

-

- -

Li-Fraumeni syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 279 of the TP53 protein (p.Gly279Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with small cell lung cancer (PMID: 33504652). This variant is also known as c.719G>A (G240E). ClinVar contains an entry for this variant (Variation ID: 419454). 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 with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 11313981, 11423991, 12826609, 16508005, 29979965, 30224644). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-7.4	D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	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
Polyphen		1.0, 1.0	.;.;.;.;.;.;.;.;D;.;D;D;D;.;.;D;.;.;.
Vest4		0.56
MutPred		0.84		Gain of solvent accessibility (P = 0.0026);.;.;.;.;.;.;.;Gain of solvent accessibility (P = 0.0026);.;Gain of solvent accessibility (P = 0.0026);Gain of solvent accessibility (P = 0.0026);Gain of solvent accessibility (P = 0.0026);.;.;Gain of solvent accessibility (P = 0.0026);.;.;.;
MVP		0.95
MPC		0.43
ClinPred		1.0	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.79

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: rs1064793881; hg19: chr17-7577102; COSMIC: COSV52677880; COSMIC: COSV52677880;