17-7673826-A-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000546.6(TP53):c.794T>A(p.Leu265Gln) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L265P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.32

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 18 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 16 uncertain in NM_000546.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-7673826-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 245777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 17-7673826-A-T is Pathogenic according to our data. Variant chr17-7673826-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 953467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.794T>A	p.Leu265Gln	missense_variant	8/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.794T>A	p.Leu265Gln	missense_variant	8/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 24, 2023	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 265 of the TP53 protein (p.Leu265Gln). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 34240179; Invitae). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu265 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9067756, 12826609, 16861262, 17606709, 20128691, 20522432, 21343334). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609). 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: 953467). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	Oct 11, 2019	Data included in classification: Absent from gnomAD (PM2_sup). Align GVGD: Class 65, Revel: 0.964. Bayes del: 0.601. TP53 ConSurf plot shows this residue to be 9 on the conservation scale (predicted to be a highly conserved and buried structural residue). (PP3_mod). Kato et al. 2003 (PMID 12826609) Transactivation class: Non functional. Giacomelli et al. 2018 (PMID 30224644) DNE and LOF variant. Fortuno et al, 2018 (PMID: 29775997) Suggested prediction: non-functional. (PS3_strong). Data not included in classification: UK Family 1: Variant identified in a child with adrenocortical cancer (1 proband meeting Chompret criteria). Pathogenic variant that affects same residue with 2* ClinVar status p.Leu265Pro (BLOSUM62: -3 compared to -2 for current variant). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 26, 2018

The p.L265Q variant (also known as c.794T>A), located in coding exon 7 of the TP53 gene, results from a T to A substitution at nucleotide position 794. The leucine at codon 265 is replaced by glutamine, an amino acid with dissimilar properties. This variant is located in the highly-conserved DNA binding domain of the p53 protein and is reported to have loss of transactivation capacity in yeast based assays (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Another alteration at this same position (p.L265P) was identified in a family with Li Fraumeni Syndrome, and was demonstrated to have reduced DNA binding capability (Cornelis RS et al. Hum. Mutat. 1997;9(2):157-63; Malcikova et al. J. Biol. Chem. 391(2-3):197-205). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature. 2016 08;536:285-91), and is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	32
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.99	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	0.55	T
PROVEAN	Pathogenic	-5.3	D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
REVEL	Pathogenic	0.96
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	.;.;.;.;.;.;.;.;D;.;D;D;D;.;.;D;.;.;.
Vest4		0.95
MutPred		0.94		Gain of disorder (P = 0.1073);.;.;.;.;.;.;.;Gain of disorder (P = 0.1073);.;Gain of disorder (P = 0.1073);Gain of disorder (P = 0.1073);Gain of disorder (P = 0.1073);.;.;Gain of disorder (P = 0.1073);.;.;.;
MVP		1.0
MPC		0.39
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.32		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs879253942; hg19: chr17-7577144; COSMIC: COSV53696163; COSMIC: COSV53696163;