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17-7674251-A-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PS1_Very_StrongPM1PM2PM5PP3_StrongPP5

The NM_000546.6(TP53):​c.712T>A​(p.Cys238Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,758 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C238F) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 30)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

16
1
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 9.23
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 ACMG points.

PS1
Transcript NM_000546.6 (TP53) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 376575
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 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 chr17-7674250-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, 0.994
PP5
Variant 17-7674251-A-T is Pathogenic according to our data. Variant chr17-7674251-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 485039.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TP53NM_000546.6 linkuse as main transcriptc.712T>A p.Cys238Ser missense_variant 7/11 ENST00000269305.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TP53ENST00000269305.9 linkuse as main transcriptc.712T>A p.Cys238Ser missense_variant 7/111 NM_000546.6 P1P04637-1

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461758
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727192
show subpopulations
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
30

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJan 06, 2021The p.C238S pathogenic mutation (also known as c.712T>A), located in coding exon 6 of the TP53 gene, results from a T to A substitution at nucleotide position 712. The cysteine at codon 238 is replaced by serine, an amino acid with dissimilar properties. This variant was detected in a classic LFS family, where the proband had leiomyosarcoma, his brother had colon cancer at 28, and his two nieces had brain cancer at ages 13 and 8 (Balmaña J, Med Clin (Barc) 2002 Oct; 119(13):497-9). This variant is reported to have loss of transactivation capacity and a dominant negative effect in yeast based functional assays (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Monti P et al. Mol. Cancer Res. 2011 Mar;9(3):271-9). 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). In addition, this variant is in the DNA binding domain of the TP53 protein and is one of four cysteine 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 decrease in structural stability (Cho Y, Science 1994 Jul; 265(5170):346-55). Several other alterations at this amino acid position (p.C238R, 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; Monti P et al. Mol. Cancer Res. 2011 Mar;9(3):271-9); internal Ambry data). 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. -
Li-Fraumeni syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeNov 30, 2023This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 238 of the TP53 protein (p.Cys238Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni Syndrome (PMID: 12406399, 34240179). ClinVar contains an entry for this variant (Variation ID: 485039). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. 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. -

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
26
DANN
Uncertain
0.99
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
0.98
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
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-9.5
D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D
REVEL
Pathogenic
0.96
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 = 0.0048);Gain of disorder (P = 0.0048);.;.;.;.;.;.;.;Gain of disorder (P = 0.0048);.;Gain of disorder (P = 0.0048);Gain of disorder (P = 0.0048);Gain of disorder (P = 0.0048);.;.;Gain of disorder (P = 0.0048);.;.;.;.;
MVP
0.99
MPC
0.42
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
0.93

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1057519981; hg19: chr17-7577569; COSMIC: COSV52699956; COSMIC: COSV52699956; API