17-7674193-A-T

Position:

• chr17-7674193-A-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.770T>A​(p.Leu257Gln) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• 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]

TP53 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a region_of_interest Interaction with AXIN1 (size 176) in uniprot entity P53_HUMAN there are 53 pathogenic changes around while only 3 benign (95%) in NM_000546.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 17-7674193-A-T is Pathogenic according to our data. Variant chr17-7674193-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 12372.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.770T>A	p.Leu257Gln	missense_variant	7/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.770T>A	p.Leu257Gln	missense_variant	7/11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Li-fraumeni-like syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1995

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 25, 2020

The p.L257Q pathogenic mutation (also known as c.770T>A), located in coding exon 6 of the TP53 gene, results from a T to A substitution at nucleotide position 770. The leucine at codon 257 is replaced by glutamine, an amino acid with dissimilar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (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 and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This variant was not reported in population-based 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. -

Ovarian neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

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

Dec 01, 2018

- -

Li-Fraumeni syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 15, 2023

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. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 17606709, 20128691, 21343334). 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: 12372). This missense change has been observed in individual(s) with sarcoma (PMID: 8134127). 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 257 of the TP53 protein (p.Leu257Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D;D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.78	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
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.3	.;.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.2	D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	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;.;.;.
Vest4		0.97
MutPred		0.97		Loss of catalytic residue at L257 (P = 0.0431);Loss of catalytic residue at L257 (P = 0.0431);.;.;.;.;.;.;.;Loss of catalytic residue at L257 (P = 0.0431);.;Loss of catalytic residue at L257 (P = 0.0431);Loss of catalytic residue at L257 (P = 0.0431);Loss of catalytic residue at L257 (P = 0.0431);.;.;Loss of catalytic residue at L257 (P = 0.0431);.;.;.;
MVP		1.0
MPC		0.39
ClinPred		1.0	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.95

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: rs28934577; hg19: chr17-7577511; COSMIC: COSV52703253; COSMIC: COSV52703253;