rs587780075

Positions:

• chr17-7673820-C-A
• chr17-7673820-C-G
• chr17-7673820-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000546.6(TP53):​c.800G>T​(p.Arg267Leu) 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R267Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.91

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 10 ACMG points.

• PM1: In a strand (size 10) in uniprot entity P53_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) 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 chr17-7673820-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.800G>T	p.Arg267Leu	missense_variant	8/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9	c.800G>T	p.Arg267Leu	missense_variant	8/11	1	NM_000546.6	ENSP00000269305	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 24, 2021

This sequence change replaces arginine with leucine at codon 267 of the TP53 protein (p.Arg267Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. 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. This variant disrupts the p.Arg267 amino acid residue in TP53. Other variant(s) that disrupt this residue have been observed in individuals with TP53-related conditions (PMID: 25584008, 28573494, 29324801, 30588330; Invitae), which suggests that this may be a clinically significant amino acid residue. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TP53 protein function (PMID: 12826609, 29979965, 30224644). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function. ClinVar contains an entry for this variant (Variation ID: 852206). This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is not present in population databases (ExAC no frequency). -

Adrenocortical carcinoma, hereditary Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;T;T;T;T;T;T;.;.;.;T;T;.;T;T;T;T;T;T
M_CAP	Pathogenic	0.77	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	1.0	D
MutationAssessor	Pathogenic	3.2	.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.5	D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0040	D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
Sift4G	Pathogenic	0.0010	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		0.96
MutPred		0.93		Loss of disorder (P = 0.0507);.;.;.;.;.;.;.;Loss of disorder (P = 0.0507);.;Loss of disorder (P = 0.0507);Loss of disorder (P = 0.0507);Loss of disorder (P = 0.0507);.;.;Loss of disorder (P = 0.0507);.;.;.;
MVP		0.99
MPC		0.41
ClinPred		1.0	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs587780075; hg19: chr17-7577138; COSMIC: COSV52675189; COSMIC: COSV52675189;