TP53 c.535C>A, p.His179Asn
NM_000546.6:c.535C>A
COSMIC ID: COSM44151
Pathogenic
Under TP53 VCEP guidelines, only PM2_Supporting is met (very low population frequency) and no other criteria at moderate or strong level apply; thus the variant remains a VUS.
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.535C>A
Protein Change
H179N
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 179 in gene TP53
Alternate Identifiers
COSM44151
Variant interpretation based on transcript NM_000546.6
Genome Browser
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HGVS InputNM_000546:c.535C>A
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000398%
Extremely Rare
Highest in Population
European (non-Finnish)
0.00088%
Very Rare
Global: 0.000398%
European (non-Finnish): 0.00088%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 251304Alt: 1Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000398%, 1/251304 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.00088%, 1/113610 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
3 publications
Likely Pathogenic
Based on 4 submitter reviews in ClinVar
Submitter Breakdown
3 LP
1 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (3)
The p.H179N variant (also known as c.535C>A), located in coding exon 4 of the TP53 gene, results from a C to A substitution at nucleotide position 535. The histidine at codon 179 is replaced by asparagine, an amino acid with similar properties. 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 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 is one of four amino acid residues required for zinc binding and protein stabilization (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 et al. Science. 1994 Jul; 265(5170):346-55). 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 majority of available evidence to date, this variant is likely to be pathogenic.
This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 179 of the TP53 protein (p.His179Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 376609). 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%. Experimental studies have shown that this missense change affects TP53 function (PMID: 8633021, 9290701, 10616528, 12826609, 16861262, 19462533, 29979965). 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.
This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 27813088, 19462533]. This variant is expected to disrupt protein structure [Myriad internal data].
Clinical Statement
This variant has been reported in ClinVar as Likely pathogenic (3 clinical laboratories) and as Uncertain significance (1 clinical laboratories).
COSMIC ID
COSM44151
Recurrence
39 occurrences
PM1 Criteria
Applied
Criterion PM1 is applied based on the high recurrence in COSMIC database.
COSMIC Database Preview
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Functional Impact
Functional Domain
Hotspot Status
Hotspot
PM1
Mutation Count
1043
Reported mutations in this domain
050100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (1043 mutations).
PM1 criterion applied.
Related Variants in This Domain
No evidence of other pathogenic variants at position 179 in gene TP53
Functional Summary
The TP53 H179N variant has been functionally characterized and is likely damaging. In vitro studies demonstrate that this mutation results in reduced DNA binding activity and decreased activation of TP53 target genes. Additionally, it shows a diminished apoptotic response to X-ray exposure in model organisms and similar exonuclease activity compared to the wild-type protein. These findings suggest an inactivating effect on TP53's tumor suppressor function.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.902
0.902
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
Yes
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damagingmetasvm: Dmetalr: D
Benign:
CADD: 5.37primateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PVS1 is: 'Apply to predicted null variants causing loss of function as per the TP53 PVS1 decision tree.' The evidence for this variant shows it is a missense change (p.H179N) not predicted to create a null allele. Therefore, this criterion is not applied because the variant type does not meet PVS1 requirements.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: 'Strong: same amino acid change as a previously established pathogenic variant following TP53 VCEP specifications.' The evidence for this variant shows p.H179N has no identical amino acid change previously classified as pathogenic under VCEP. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: 'Points-based de novo evidence for pathogenicity.' The evidence for this variant shows no information on de novo occurrence or parental genotypes. Therefore, PS2 is not applied due to lack of de novo data.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: 'Strong: Non-functional on Kato et al. data AND loss of function on another assay.' The evidence for this variant shows general functional impairment in vitro but does not specify results from Kato et al. or other named assays per the VCEP scheme. Therefore, PS3 is not applied because the assays required for VCEP-level assessment are not documented.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: 'Points-based case-level data for probands with TP53-associated cancers.' The evidence for this variant shows no reported case counts or proband data. Therefore, PS4 is not applied due to absence of clinical case evidence.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: 'Moderate for missense variants within codons 175, 245, 248, 249, 273, or 282.' The evidence for this variant shows it occurs at codon 179, which is not listed as a VCEP-defined hotspot. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: 'Supporting: allele frequency <0.00003 (0.003%) in gnomAD.' The evidence for this variant shows MAF = 0.000398% (0.00000398), which is below the threshold. Therefore, PM2 is applied at Supporting strength because the allele frequency meets the VCEP supporting threshold.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'For recessive disorders, detected in trans with a pathogenic variant.' The evidence for this variant shows no data on trans observations in a recessive context for TP53. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes due to in-frame indels or stop-loss variants.' The evidence shows this is a missense variant with no length change. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: 'Moderate if ≥1 different missense variant at the same residue is classified as pathogenic by TP53 VCEP.' The evidence shows no documented different pathogenic missense variants at codon 179 per VCEP records. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: 'Unconfirmed de novo occurrence.' The evidence shows no de novo information. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: 'Supporting to Strong based on segregation in families.' The evidence shows no segregation data. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with low benign variation.' TP53 is known for both benign and pathogenic missense changes and no specific VCEP PP2 recommendation is provided. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: 'Supporting: BayesDel score ≥0.16 and no predicted splice impact.' The evidence shows a REVEL score but no BayesDel data. Therefore, PP3 is not applied due to lack of VCEP-specified computational metrics.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Patient’s phenotype or family history highly specific for a disease with a single genetic etiology.' The evidence shows no specific phenotypic correlation data. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports as pathogenic without available evidence.' ClinVar entries exist, but ACMG recommends caution and VCEP provides no PP5. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: 'Stand Alone if allele frequency ≥0.001 (0.1%).' The evidence shows MAF = 0.000398%, below the cutoff. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: 'Strong if filtering allele frequency ≥0.0003 but <0.001 in a single ancestry.' The evidence shows MAF = 0.000398% (0.00000398), which is below 0.0003. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: 'Evidence of unaffected older individuals.' The evidence shows no such observations. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: 'Strong if functional data shows no loss of function.' The evidence shows loss of DNA binding and apoptotic response. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: 'Lack of segregation in affected members.' The evidence shows no segregation data. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'Missense in a gene where only truncating variants cause disease.' TP53 pathogenicity often involves missense changes. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant for a recessive disorder or in cis with a pathogenic variant.' The evidence shows no such data. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame indels in repetitive region without functional impact.' The evidence shows a missense variant, not an indel. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: 'Supporting if BayesDel <0.16 and no splicing impact.' The evidence shows no BayesDel data and predicted damaging impact. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: 'Variant found in a case with an alternative molecular cause.' No such alternative cause is documented. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign without evidence.' No such benign assertions exist. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: 'Synonymous or intronic variant with no splice impact.' This variant is missense. Therefore, BP7 is not applied.