TP53 c.461G>A, p.Gly154Asp
NM_000546.6:c.461G>A
COSMIC ID: COSM45622
Likely Pathogenic
This legacy system is being phased out as Project HERA V3 is rolled out.
ACMG/AMP Criteria Applied
PM2
Genetic Information
Gene & Transcript Details
Gene
TP53
Transcript
NM_000546.6
MANE Select
Total Exons
11
Strand
Reverse (−)
Reference Sequence
NC_000017.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000546.5 | RefSeq Select | 11 exons | Reverse |
| NM_000546.3 | Alternative | 11 exons | Reverse |
| NM_000546.4 | Alternative | 11 exons | Reverse |
| NM_000546.2 | Alternative | 11 exons | Reverse |
Variant Details
HGVS Notation
NM_000546.6:c.461G>A
Protein Change
G154D
Location
Exon 5
(Exon 5 of 11)
5'Exon Structure (11 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 154 in gene TP53
Alternate Identifiers
COSM45622
Variant interpretation based on transcript NM_000546.6
Genome Browser
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HGVS InputNM_000546:c.461G>A
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000796%
Very Rare
Highest in Population
European (non-Finnish)
0.00176%
Rare
Global: 0.000796%
European (non-Finnish): 0.00176%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 251272Alt: 2Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000796%, 2/251272 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.00176%, 2/113600 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
5 publications
Likely Pathogenic
Based on 10 submitter reviews in ClinVar
Submitter Breakdown
1 LP
9 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (5)
Variant summary: TP53 c.461G>A (p.Gly154Asp) results in a non-conservative amino acid change located in the p53, DNA-binding domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251272 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.461G>A has been reported in the literature in an individual with a personal and family history of breast cancer (Zanti_2020). This report does not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. Publications report experimental evidence evaluating an impact on protein function, showing either partially reduced function or no deleterious effect (e.g. Kato_2003, Giacomelli_2018, Kotler_2018). The following publications have been ascertained in the context of this evaluation (PMID: 33120919, 12826609, 30224644, 29979965). ClinVar contains an entry for this variant (Variation ID: 237950), including an evaluation from a ClinGen expert panel which classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
This missense variant replaces glycine with aspartic acid at codon 154 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant functional in transactivation and cell growth and proliferation assays (PMID: 12826609, 329979965, 0224644). This variant has been reported in an individuals affected with triple negative breast cancer s in the literature (PMID: 33120919). This variant has been identified in 2/251272 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
The p.G154D variant (also known as c.461G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 461. The glycine at codon 154 is replaced by aspartic acid, an amino acid with similar properties. This variant has been reported in a cohort of triple negative breast cancer patients from Cyprus (Zanti M et al. Cancers (Basel), 2020 Oct;12:). In another study, this variant was reported in 0/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant is in the DNA binding domain of the TP53 protein and is reported to have partially 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 proficient at growth suppression and has no 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). Based on internal structural analysis, this variant is not anticipated to result in a significant decrease in structural stability (Cho Y, Science 1994 Jul; 265(5170):346-55). In addition, this alteration did not segregate with disease in one family tested in our laboratory (Ambry internal data). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 154 of the TP53 protein (p.Gly154Asp). This variant is present in population databases (rs762846821, gnomAD 0.002%). This missense change has been observed in individual(s) with acute myeloid leukemia and/or triple negative breast cancer (PMID: 27276561, 33120919). ClinVar contains an entry for this variant (Variation ID: 237950). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 29979965, 30224644). 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.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (9 clinical laboratories) and as Likely pathogenic (1 clinical laboratories) and as Uncertain Significance by ClinGen TP53 Variant Curation Expert Panel, ClinGen expert panel.
Expert Panel Reviews
Uncertain Significance
ClinGen TP53 Variant Curation Expert Panel, ClinGen
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 154 in gene TP53
Functional Summary
The TP53 G154D variant has been functionally characterized and demonstrated to be inactivating. In vivo studies using yeast models have shown that this mutation results in a partial loss of transactivational activity compared to the wildtype, indicating a damaging effect on the protein's function.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Pathogenic:
metasvm: Dmetalr: D
Benign:
CADD: 2.45polyphen_prediction: benignprimateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, "PVS1 not applicable or not evaluated." The evidence for this variant shows it is a missense change (G154D), not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, "PS1 can be applied to variants asserted as Pathogenic following the TP53 VCEP’s specifications." The evidence for this variant shows no other variant at codon 154 classified as Pathogenic. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, "PS2 requires de novo confirmation with points-based system (Very Strong ≥8 points, Strong 4–7 points, etc.)." No de novo data are available for this variant. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, "PS3_Strong: Non-functional on Kato et al. data AND loss of function on another assay. PS3_Moderate: Partially functional on Kato et al. data AND LOF on Giacomelli et al. data AND/OR another assay." The evidence shows a single yeast model assay with partial loss of transactivational activity, but no Kato or Giacomelli data. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, "PS4 requires case points (Very Strong ≥8 points, Strong 4–7.5 points, etc.)." No proband or case-level data are available. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, "PM1: Moderate for missense variants within hotspot codons 175, 245, 248, 249, 273, 282." Codon 154 is outside these hotspots. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, "PM2: Supporting. Apply when allele frequency <0.00003 in gnomAD or another large population database." The evidence shows MAF=0.00000796 (0.000796%), which is below 0.00003. Therefore, PM2 is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM3 applies to recessive disorders with variants detected in trans. TP53-associated disease is dominant and no trans data are available. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 applies to protein length changes such as in-frame indels. This is a missense variant without indel or splicing alteration. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, "PM5: Moderate for missense variants at a residue with ≥1 other pathogenic variant." No other pathogenic missense variants at codon 154 are documented. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, "PM6: De novo without confirmation of paternity/maternity (points-based)." No de novo data are available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, "PP1 requires cosegregation evidence across meioses (Supporting 3–4, Moderate 5–6, Strong ≥7)." No family segregation data are available. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies to genes with low rate of benign missense variation and where missense is common mechanism. TP53 has many benign and pathogenic missense variants. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, "PP3: Moderate when BayesDel ≥0.16 and no predicted splice effect; Supporting at lower thresholds." BayesDel score is not provided and computational predictions are mixed. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, "PP4 requires disease-specific phenotype observations." No phenotype or tumor VAF data are provided. Therefore, PP4 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, "BA1: Stand Alone when allele frequency ≥0.001 in gnomAD subpopulation." MAF is 0.00000796, below threshold. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, "BS1: Strong when allele frequency ≥0.0003 but <0.001." MAF is 0.00000796, below 0.0003. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, "BS2: Strong when ≥8 unaffected older females without cancer are observed." No such data are available. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, "BS3 applies when functional assays show preserved function on Kato and another assay." The variant shows partial loss of function. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, "BS4: Strong when lack of segregation in affected family members." No segregation data exist. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 applies to missense variants in a gene where only truncating variants are pathogenic. TP53 has many pathogenic missense variants. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies when variant is in trans with a pathogenic variant in recessive disorder. TP53 disease is dominant. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. This is a missense variant. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, "BP4: Moderate when BayesDel ≤ –0.008 and no predicted splicing impact; Supporting for BayesDel <0.16 and no splicing effect." BayesDel score is not available and evidence is mixed. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 applies when variant found in case with other pathogenic variant. No such evidence is provided. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to ACMG guidelines, BP6 applies to reputable source assertion of benign without evidence. ClinVar entries are conflicting (uncertain and likely pathogenic). Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 applies to synonymous or intronic variants with no splicing impact. This variant is missense. Therefore, BP7 is not applied.