17-7673820-C-G

Position:

• chr17-7673820-C-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The ENST00000269305.9(TP53):​c.800G>C​(p.Arg267Pro) 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R267Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TP53 ENST00000269305.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• 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 11 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, 16 uncertain in ENST00000269305.9
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-7673821-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 1761541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 17-7673820-C-G is Pathogenic according to our data. Variant chr17-7673820-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 428867.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.800G>C	p.Arg267Pro	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>C	p.Arg267Pro	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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2022

The p.R267P pathogenic mutation (also known as c.800G>C), located in coding exon 7 of the TP53 gene, results from a G to C substitution at nucleotide position 800. The arginine at codon 267 is replaced by proline, an amino acid with dissimilar properties. This variant has been reported in multiple BRCA1/2-negative breast cancer patients (Hauke J et al. Cancer Med. 2018 04;7:1349-1358; Grill S et al. Arch Gynecol Obstet. 2021 06;303:1557-1567). This variant has also been reported in the germline of one female patient diagnosed with an adrenocortical carcinoma at age 1 and then diagnosed with ALL at age 12 (Winter G et al. Leukemia. 2021 05;35:1475-1479). 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). Another alteration at the same codon, p.R267W (c.799C>T), has been reported in several patients meeting either classic Li-Fraumeni syndrome (LFS) criteria or Chompret criteria (Melhem-Bertrandt A et al. Cancer 2012 Feb;118(4):908-13; Stoltze U et al. PLoS ONE, 2018 Jan;13:e0190050; Llovet P et al. Fam. Cancer. 2017 Oct;16(4):567-575; AlHarbi M et al. NPJ Genom Med. 2018 Dec 19;3:35). Yet another alteration at this same position, p.R267Q, has been described in a non-classical Li-Fraumeni syndrome (LFS) family as well as in a child with multiple tumors from an LFS family who was found to harbor three TP53 alterations: R156H, R267Q, and R290H (Prosser et al. Br J Cancer. 1992 Apr;65(4):527-8; Quesnel et al. Oncogene. 1999 Jul 8;18(27):3970-8). The p.R267P variant is considered to be rare based on population 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. -

Acute myeloid leukemia Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Ayesha Lab, University of the Punjab

-

- -

Li-Fraumeni syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 28, 2019

This variant disrupts the p.Arg267 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21761402, 27501770, 28573494, 29324801, 30588330, 16861262, 24076587, 12826609). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant is not present in population databases (ExAC no frequency). 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. An experimental study in yeast has shown that this variant impairs the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). In addition, experimental studies using a lung cancer cell line that carries this variant demonstrates elevated Axl expression and enhanced cell growth, while p21 promoter activity appears unaffected (PMID: 23264849, 22989750). This variant has not been reported as a germline variant in individuals affected with TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 428867). This sequence change replaces arginine with proline at codon 267 of the TP53 protein (p.Arg267Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	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
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	0.63	T
PROVEAN	Pathogenic	-6.5	D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	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		0.97
MutPred		0.92		Loss of catalytic residue at R267 (P = 0.049);.;.;.;.;.;.;.;Loss of catalytic residue at R267 (P = 0.049);.;Loss of catalytic residue at R267 (P = 0.049);Loss of catalytic residue at R267 (P = 0.049);Loss of catalytic residue at R267 (P = 0.049);.;.;Loss of catalytic residue at R267 (P = 0.049);.;.;.;
MVP		0.99
MPC		0.45
ClinPred		1.0	D
GERP RS		3.1
Varity_R		1.0
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: COSV52691512; COSMIC: COSV52691512;