17-7674251-A-G

Position:

• chr17-7674251-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000269305.9(TP53):​c.712T>C​(p.Cys238Arg) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C238S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 30)
• Consequence: TP53 ENST00000269305.9 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.23

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 18 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 14 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 chr17-7674250-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 17-7674251-A-G is Pathogenic according to our data. Variant chr17-7674251-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6	c.712T>C	p.Cys238Arg	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.712T>C	p.Cys238Arg	missense_variant	7/11	1	NM_000546.6	ENSP00000269305	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Li-Fraumeni syndrome 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 16, 2024	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 7478555, 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 05, 2023	The p.C238R pathogenic mutation (also known as c.712T>C), located in coding exon 6 of the TP53 gene, results from a T to C substitution at nucleotide position 712. The cysteine at codon 238 is replaced by arginine, an amino acid with highly dissimilar properties. Although this specific alteration has not been reported in the literature, several other alterations at this amino acid position (p.C238S, p.C238G and p.C238Y) have been reported in patients with Li-Fraumeni or Li-Fraumeni-Like syndrome and classified as severe deficiency alleles based on functional studies (Kurtilkova et al Eur J Cancer. 2005 Jul;41(11):1597-603; Balmaña J et al. Med Clin (Barc) 2002 Oct;119(13):497-9; Monti P et al. Mol. Cancer Res. 2011 Mar;9(3):271-9); internal Ambry data). This variant is reported to have loss of transactivation capacity in yeast based functional assays (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9). This alteration is located in the DNA binding domain of the TP53 protein and is one of four residues involved in binding a zinc atom necessary for the protein to adopt the correct conformation (Martin et al Hum. Mutat. 2002 Feb;19(2):149-64). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Cho Y, Science 1994 Jul; 265(5170):346-55). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis.This amino acid position is highly conserved in available vertebrate species. Based on the available evidence, p.C238R is classified as a pathogenic mutation. -

Li-Fraumeni syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 03, 2019

An experimental study in yeast has shown that this variant impairs the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). This variant has been observed to be de novo in an individual affected with choroid plexus carcinoma (Invitae). ClinVar contains an entry for this variant (Variation ID: 376576). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 238 of the TP53 protein (p.Cys238Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant disrupts the p.C238 amino acid residue in TP53. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID:  12406399, 14673037, 15925506), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;D;.;.;.;.;D;D;.;D;.;.;.;.;.;.;D;.;.;.;D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.93	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;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	3.3	.;.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-11	D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;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;.;.;.;D
Vest4		0.98
MutPred		0.98		Gain of disorder (P = 0.0226);Gain of disorder (P = 0.0226);.;.;.;.;.;.;.;Gain of disorder (P = 0.0226);.;Gain of disorder (P = 0.0226);Gain of disorder (P = 0.0226);Gain of disorder (P = 0.0226);.;.;Gain of disorder (P = 0.0226);.;.;.;.;
MVP		0.99
MPC		0.50
ClinPred		1.0	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		1.0
gMVP		0.96

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: rs1057519981; hg19: chr17-7577569; COSMIC: COSV52707471; COSMIC: COSV52707471;