17-7675200-C-G
Position:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000546.6(TP53):c.412G>C(p.Ala138Pro) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A138S) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 33)
Consequence
TP53
NM_000546.6 missense
NM_000546.6 missense
Scores
13
4
2
Clinical Significance
Conservation
PhyloP100: 7.90
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 18 ACMG points.
PM1
In a region_of_interest Interaction with AXIN1 (size 176) in uniprot entity P53_HUMAN there are 53 pathogenic changes around while only 3 benign (95%) 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 chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.988
PP5
Variant 17-7675200-C-G is Pathogenic according to our data. Variant chr17-7675200-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 12376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 35
GnomAD4 exome
Cov.:
35
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Li-Fraumeni syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 15, 2025 | This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 138 of the TP53 protein (p.Ala138Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Li-Fraumeni syndrome-related cancers (adrenocortical carcinoma, rhabdomyosarcoma, chondrosarcoma, breast cancer) (PMID: 9569035, 17567834). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12376). Invitae Evidence Modeling incorporating data from in vitro 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%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 15548685, 17606709, 19958544, 21343334). This variant disrupts the p.Ala138 amino acid residue in TP53. Other variant(s) that disrupt this residue have been observed in individuals with TP53-related conditions (PMID: 22507745, 32552660), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Li-Fraumeni syndrome 1 Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 1998 | - - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 01, 2023 | Published functional studies demonstrate a damaging effect: non-functional transactivation and loss of growth suppression ability (PMID: 12826609, 21343334, 29979965, 30224644); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17606709, 30840781, 15548685, 18765419, 20118236, 25847421, 30224644, 21343334, 19958544, 17567834, 25584008, 29753700, 29979965, 15510160, 9569035, 12826609) - |
Hereditary cancer-predisposing syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 23, 2024 | The p.A138P pathogenic mutation (also known as c.412G>C), located in coding exon 4 of the TP53 gene, results from a G to C substitution at nucleotide position 412. The alanine at codon 138 is replaced by proline, an amino acid with highly similar properties. This alteration has been identified in a family meeting Li-Fraumeni syndrome criteria (Sedlacek Z et al. Br J Cancer, 1998 Apr;77:1034-9) and also in two related individuals with medulloblastoma (Waszak SM et al. Lancet Oncol, 2018 06;19:785-798). 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). This variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;D;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T;T;T;T;.;.;.;T;T;.;T;T;T;T;T;T;T;T;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D;D;.
REVEL
Pathogenic
Sift
Uncertain
D;D;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D;D;.
Sift4G
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;.;D
Polyphen
D;.;.;.;.;.;D;.;D;D;D;.;.;D;.;.;.;D;.;.
Vest4
MutPred
Loss of helix (P = 0.079);Loss of helix (P = 0.079);.;.;.;.;Loss of helix (P = 0.079);.;Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);.;.;Loss of helix (P = 0.079);.;.;.;.;Loss of helix (P = 0.079);.;
MVP
MPC
1.9
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at