17-7670657-T-C

Position:

• chr17-7670657-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The ENST00000269305.9(TP53):​c.1052A>G​(p.Lys351Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K351E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TP53 ENST00000269305.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.836

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 3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 10 benign, 15 uncertain in ENST00000269305.9
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3234678).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.1052A>G	p.Lys351Arg	missense_variant	10/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.1052A>G	p.Lys351Arg	missense_variant	10/11	1	NM_000546.6	ENSP00000269305	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461812 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727194

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: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Li-Fraumeni syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 10, 2017

Experimental studies have shown that this missense change does not appreciably affect TP53 protein function (PMID: 12826609, 27297285). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TP53-related disease. This sequence change replaces lysine with arginine at codon 351 of the TP53 protein (p.Lys351Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	.;.;.;D;.;D;.;.
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	D;D;.;.;.;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.32	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.58	D
MutationAssessor	Uncertain	2.4	.;.;.;M;.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.59	.;.;.;N;.;N;.;.
REVEL	Uncertain	0.37
Sift	Benign	0.29	.;.;.;T;.;T;.;.
Sift4G	Benign	0.51	T;T;T;T;T;T;T;T
Polyphen		0.63	.;.;.;P;.;P;.;.
Vest4		0.15
MutPred		0.36		.;.;.;Loss of ubiquitination at K351 (P = 0.0047);.;Loss of ubiquitination at K351 (P = 0.0047);.;.;
MVP		0.92
MPC		0.10
ClinPred		0.38	T
GERP RS		4.4
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.9
Varity_R		0.23
gMVP		0.26

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: rs1555524396; hg19: chr17-7573975; COSMIC: COSV53304065; COSMIC: COSV53304065;