The TP53 c.319T>C (p.Tyr107His) variant has been observed in somatic cancers with 2 COSMIC observations and has been reported in ClinVar with a Benign expert-panel classification from the ClinGen TP53 Variant Curation Expert Panel.1 This variant is present in gnomAD above the TP53 PM2 threshold and within the TP53 BS1 range, with grpmax filtering allele frequencies of 0.000795 in gnomAD v2.1 and 0.000794 in gnomAD v4.1.2 In the TP53 VCEP functional worksheet, Y107H is recorded as partially functional with no loss of function in other eligible assay columns, supporting BS3_Supporting and arguing against PS3.3 TP53-specific in silico assessment assigns BP4 for c.319T>C; BayesDel is 0.020196, SpliceAI predicts no splice impact with a max delta score of 0.00, and the available computational evidence does not support PP3.4
Final classification
Benign
BS1BS3BP4BP6
TP53
c.319T>C
p.Tyr107His
This variant
The TP53 c.319T>C (p.Tyr107His) variant has been observed in somatic cancers with 2 COSMIC observations and has been reported in ClinVar with a Benign expert-panel classification from the ClinGen TP53 Variant Curation Expert Panel.
TP53 ClinGen VCEP v2.4.0 Tavtigian point-based final-classification framework
Classification rationale
BS1BS3BP4BP6
Benign
TP53 c.319T>C
BS1 + BS3 + BP4 + BP6
→
Benign
3
vcep_functional_worksheetvcep_flowchart_for_application_of_functional_rule_codesPMID:12826609 ↗PMID:30224644 ↗
4
vcep_pp3_bp4_codesvcep_flowchart_for_application_of_pp3_2c_bp4_2c_and_bp7bayesdelspliceai ↗revel
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_000546.5 · variants mapped to exon structure
TP53
NM_000546.5
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 13 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
BS1
strong
Benign
This variant meets TP53 BS1 because its filtering allele frequency is above the BS1 threshold of 0.0003 but below the BA1 threshold of 0.001. The highest observed grpmax FAF is 0.000795 in gnomAD v2.1 and 0.000794 in gnomAD v4.1, with the highest population frequency in African/African American individuals.
gnomAD v2 grpmax FAF 0.00079507African/African American AF 0.00112233gnomAD v4 grpmax FAF 0.00079357
BS3
supporting
Benign
Published TP53 functional evidence supports BS3_Supporting for this variant. In the TP53 functional worksheet, Y107H is listed as partially functional with no loss of function in other eligible assay columns, and the pre-assigned TP53 VCEP code is BS3_Supporting.
Functional worksheet pre-assigned code BS3_SupportingAssay summary recorded as partially functional and noLOF
BP4
supporting
Benign
Computational evidence supports TP53 BP4. The TP53 VCEP in silico worksheet assigns BP4 for c.319T>C, the BayesDel score is 0.020196, which is below the TP53 PP3 threshold of 0.16 and above the BP4_Moderate cutoff of -0.008, and SpliceAI predicts no splice effect with a max delta score of 0.00.
Precomputed TP53 VCEP code: BP4PP3-BP4 worksheet row: c.319T>C | p.Tyr107His | Class C0 | 0.020196 | BP4 | 0.04SpliceAI max delta score 0.00
Assessed · not applied
· 6 not met · 7 not assessed
Pathogenic
PS1
No same-amino-acid pathogenic TP53 comparator was confirmed for this codon, so PS1 was not assessed.
PS2
No confirmed de novo observation with the TP53-specific clinical details and parental confirmation required for PS2 was identified.
PS3
TP53 functional evidence does not support a damaging loss-of-function interpretation for this variant.
PS4
Available evidence does not support PS4.
PM1
Available evidence does not support PM1.
PM2
This variant is too common for TP53 PM2_Supporting.
PM5
PM5 was not assessed because no verified same-residue TP53 pathogenic or likely pathogenic comparator set was confirmed for codon 107 in the reviewed materials.
PP1
No segregation data were identified to show co-segregation of this variant with Li-Fraumeni syndrome-associated disease across informative meioses.
PP3
Computational evidence does not support PP3 for this TP53 missense variant.
PP4
No qualifying low-variant-allele-fraction constitutional mosaic observations were identified for this variant, so TP53-specific PP4 was not assessed.
Benign
BA1
This variant does not meet TP53 BA1 because the observed filtering allele frequency does not reach the BA1 threshold of 0.001.
BS2
No single-source dataset of unaffected older female carriers was identified to support BS2.
BS4
No family data were identified to demonstrate lack of segregation with Li-Fraumeni syndrome-associated disease.
N/A · 11
PVS1 · PM3 · PM4 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP5 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 5.58132e-05; MAF= 0.00558%, 90/1612522 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000973411; MAF= 0.09734%, 73/74994 alleles, homozygotes = 0); grpmax FAF= 0.00079357.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.000120254; MAF= 0.01203%, 34/282734 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.00112233; MAF= 0.11223%, 28/24948 alleles, homozygotes = 0); grpmax FAF= 0.00079507.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0056%
· 90 / 1,612,522
0 hom · FAF 0.079%
0 hom · FAF 0.079%
African/African American 73 / 74,994 |
0.097% |
Remaining individuals 10 / 62,354 |
0.016% |
Admixed American 7 / 60,016 |
0.012% |
+ 7 not observed (European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish))
gnomAD v2.1
0.012%
· 34 / 282,734
0 hom · FAF 0.08%
0 hom · FAF 0.08%
African/African American 28 / 24,948 |
0.11% |
Admixed American 6 / 35,434 |
0.017% |
+ 6 not observed (Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Likely benign (10 clinical laboratories) and as Benign (3 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as Benign by ClinGen TP53 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 140786)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.569. BayesDel score = 0.020196.
Functional
Likely Oncogenic
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. TP53, a tumor suppressor in the DNA damage pathway, is the most frequently mutated gene in cancer.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV53179040, n = 2 times).
Hotspots
This variant lies in a statistically significant hotspot.
Literature · how each cited paper was used
2papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 4 further PMIDs triaged but not cited — see Sources & references.
Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis.
Found
Structured finding pending for this record — see source link.
Applied to
→BS3
supporting
Mutational processes shape the landscape of TP53 mutations in human cancer.
Found
Structured finding pending for this record — see source link.
Applied to
→BS3
supporting
Sources & reference links
Triaged references · 4 PMIDs not cited in assessment
29979965 ↗
A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation.
ONCOKB
16061860 ↗
FGFR3 and Tp53 mutations in T1G3 transitional bladder carcinomas: independent distribution and lack of association with prognosis.
ONCOKB
27328919 ↗
TP53 Variations in Human Cancers: New Lessons from the IARC TP53 Database and Genomics Data.
ONCOKB
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR