Classification rationale

BS1BS3BP4BP6 Benign

TP53 c.319T>C

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

BS1 + BS3 + BP4 + BP6 → Benign

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

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

Gene diagram · NM_000546.5 · variants mapped to exon structure

TP53 NM_000546.5

Fetching transcript structure from UCSC…

Applied criteria · 4 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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%

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%

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)

gnomAD v4 ↗ gnomAD v2 ↗

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)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.569. BayesDel score = 0.020196.

SpliceAI ↗

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.

OncoKB ↗

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.

COSMIC ↗ Hotspots ↗

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. 6 further PMIDs triaged but not cited — see Sources & References.

PMID PMID:12826609

PMID PMID:12826609 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→BS3 supports · met

PMID PMID:30224644

PMID PMID:30224644 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→BS3 supports · met

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 6 PMIDs not cited in assessment

12826609 ↗ Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. ONCOKB

29979965 ↗ A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation. ONCOKB

30224644 ↗ Mutational processes shape the landscape of TP53 mutations in human cancer. 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