TP53 c.559+9C>G, p.?
NM_000546.6:c.559+9C>G
Population Frequency
0.000707%
Rare
ClinVar Classification
Likely Benign
0 publications
REVEL Score
N/A
Not Available
COSMIC Recurrence
0 occurrences
No Criteria Applied
Classification Evidence
Detailed Information
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.559+9C>G
Protein Change
?
Location
Exon 5
(Exon 5 of 11)
5'
Exon Structure (11 total)
3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_000546.6
Clinical Evidence
Global Frequency
0.000707%
Very Rare
Highest in Population
African/African American
0.00401%
Rare
Global: 0.000707%
African/African American: 0.00401%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
Allele Information
Total: 282770
Alt: 2
Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000707%, 2/282770 alleles, homozygotes = 0) and at a higher frequency in the African/African American population (MAF= 0.00401%, 1/24956 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Likely Benign
Based on 2 submitter reviews in ClinVar
Submitter Breakdown
Pathogenic
Likely Pathogenic
VUS
Likely Benign
Benign
Publications
0 publications
Clinical Statement
This variant has been reported in ClinVar as Likely benign (2 clinical laboratories).
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
Functional Studies
Summary
The TP53 559+9C>G variant has not been functionally characterized, and its biological significance remains unknown.
Computational Evidence
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 0.76
VCEP Guidelines
Applied ACMG/AMP Criteria
VCEP Guidelines
PVS1
PVS1 (Not Applied)
Strength Modified
According to VCEP guidelines for PVS1: 'Canonical splice variants (+/- 1,2 intronic positions): PVS1 applies to predicted splicing alterations that are PTC resulting in NMD or in-frame but targeting critical domains.' The evidence for this variant shows it is at +9 intronic position, outside the canonical ±1,2 splice site. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied)
Strength Modified
According to VCEP guidelines for PS1: 'Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.' The evidence for this variant shows it is intronic and does not alter an amino acid. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied)
Strength Modified
According to VCEP guidelines for PS2: 'Very Strong: ≥8 points; Strong: 4–7 points; Moderate: 2–3 points; Supporting: 1 point.' There are no de novo data for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied)
Strength Modified
According to VCEP guidelines for PS3: 'Strong: Non-functional on Kato et al. data AND loss of function on another assay; Moderate: Partially functional on Kato et al. AND loss of function on another assay; Supporting: Non-functional on Kato et al. AND abnormal on Kawaguchi et al. data or LOF on Kotler et al. data.' No functional studies have been performed for this variant. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied)
Strength Modified
According to VCEP guidelines for PS4: 'Very Strong: ≥8 points; Strong: 4–7.5 points; Moderate: 2–3.5 points; Supporting: 1–1.5 points.' There are no case-control or proband observation data for this variant. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied)
Strength Modified
According to VCEP guidelines for PM1: 'Moderate: Missense variants within codons 175, 245, 248, 249, 273, 282; Supporting: Missense variants with 2–9 somatic occurrences.' This variant is intronic and not a missense in a hotspot codon. Therefore, this criterion is not applied.
PM2
PM2 (Supporting)
Strength Modified
According to VCEP PM2: 'Supporting: Variant should have an allele frequency of less than 0.00003 (0.003%) in gnomAD.' The evidence for this variant shows a global gnomAD MAF of 0.000707%, which is below 0.003%. Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied)
Strength Modified
According to standard ACMG guidelines for PM3: 'Detected in trans with a pathogenic variant in recessive disorders.' This is a dominant gene context and no trans data are available. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied)
Strength Modified
According to standard ACMG guidelines for PM4: 'Protein length changes due to in-frame indels or stop-loss variants not known to result in LOF.' This variant is intronic and does not alter protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied)
Strength Modified
According to VCEP guidelines for PM5: 'Strong: Missense variant at residue with ≥2 pathogenic variants; Moderate: 1 pathogenic variant; Supporting: 1 likely pathogenic variant.' This variant is intronic. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied)
Strength Modified
According to VCEP guidelines for PM6: 'Unconfirmed de novo cases (without parental confirmation).' There are no unconfirmed de novo reports for this variant. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied)
Strength Modified
According to VCEP guidelines for PP1: 'Strong: Co-segregation in ≥7 meioses; Moderate: 5–6; Supporting: 3–4.' No familial segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines for PP2: 'Missense variant in a gene with low rate of benign missense variation.' This variant is intronic. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines for PP3: 'Supporting: Intronic splice variants (excluding ±1,2 positions) with SpliceAI ≥0.2.' The evidence for this variant shows a SpliceAI max score of 0.45. Therefore, this criterion is applied at Supporting strength.
PP4
PP4 (Not Applied)
Strength Modified
According to VCEP guidelines for PP4: 'Supporting: Observation with VAF 5–35%; Moderate: ≥2 observations with VAF 5–25%.' No tumor VAF or phenotype specificity data are available. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines for PP5: 'Reputable source reports variant as pathogenic without available evidence.' ClinVar reports this variant as Likely Benign, not pathogenic. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied)
Strength Modified
According to VCEP guidelines for BA1: 'Stand Alone: Filtering allele frequency ≥0.001 (0.1%) in a gnomAD continental subpopulation.' The variant MAF is 0.000707%, below 0.1%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied)
Strength Modified
According to VCEP guidelines for BS1: 'Strong: FAF ≥0.0003 but <0.001 in a gnomAD continental subpopulation.' No subpopulation has frequency ≥0.0003. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied)
Strength Modified
According to VCEP guidelines for BS2: 'Strong: ≥8 unrelated females ≥60 years without cancer; Moderate: 4–7; Supporting: 2–3.' No such cohort data are available. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied)
Strength Modified
According to VCEP guidelines for BS3: 'Strong: Functional on Kato et al. AND no LOF on another assay; Supporting: Partially functional on Kato et al. AND no LOF on other assays.' No functional data are available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied)
Strength Modified
According to VCEP guidelines for BS4: 'Strong: Lack of segregation in affected family members.' No segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines for BP1: 'Missense variant in a gene where only truncating variants cause disease.' This variant is intronic. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines for BP2: 'Observed in trans with a pathogenic variant for a dominant disorder.' No such data are available. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines for BP3: 'In-frame deletions/insertions in repetitive regions.' This variant is intronic and not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied)
Strength Modified
According to VCEP guidelines for BP4: 'Supporting: Silent or intronic outside ±1,2 positions with SpliceAI ≤0.1.' The variant has a SpliceAI score of 0.45, above the threshold. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines for BP5: 'Variant found in a case with an alternative molecular basis for disease.' No such alternative molecular basis data are available. Therefore, this criterion is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines for BP6: 'Reputable source reports variant as benign without available evidence.' ClinVar entries from two clinical laboratories report this variant as Likely Benign. Therefore, this criterion is applied at Supporting strength.
BP7
BP7 (Not Applied)
Strength Modified
According to VCEP guidelines for BP7: 'Supporting: Synonymous or intronic at or beyond +7 positions with SpliceAI ≤0.1.' The variant is at +9 but has a SpliceAI score of 0.45, above the threshold. Therefore, this criterion is not applied.