17-7674187-T-G

Position:

• chr17-7674187-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_000546.6(TP53):​c.776A>C​(p.Asp259Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D259V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.21

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 17 uncertain in NM_000546.6
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-7674187-T-G is Pathogenic according to our data. Variant chr17-7674187-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 2671888.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6	c.776A>C	p.Asp259Ala	missense_variant	7/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9	c.776A>C	p.Asp259Ala	missense_variant	7/11	1	NM_000546.6	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Malignant lymphoma, large B-cell, diffuse Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department Of Pathology & Laboratory Medicine, University Of Pennsylvania

Dec 04, 2023

Post-initial therapy specimen. This represents a loss of function missense mutation (p.D259A) previously reported in a case of esophageal carcinoma (PMID: 10414702). TP53 mutations are known drivers of DLBCL (PMID: 28985567) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T;T;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.
Eigen	Benign	0.10
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;T;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Uncertain	0.64	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	Uncertain	2.6	.;.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.13	N;N;.;.;.;.;.;.;.;N;.;.;N;N;.;.;N;.;.;N
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D;T;.;.;.;.;.;.;.;T;.;.;T;T;.;.;T;.;.;T
Sift4G	Uncertain	0.011	D;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.83	P;.;.;.;.;.;.;.;.;B;.;B;B;B;.;.;B;.;.;.
Vest4		0.64
MutPred		0.55		Loss of disorder (P = 0.0903);Loss of disorder (P = 0.0903);.;.;.;.;.;.;.;Loss of disorder (P = 0.0903);.;Loss of disorder (P = 0.0903);Loss of disorder (P = 0.0903);Loss of disorder (P = 0.0903);.;.;Loss of disorder (P = 0.0903);.;.;.;
MVP		0.95
MPC		0.39
ClinPred		0.92	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.56

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-7577505;