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LYFE SCIENCES
Project: HERA
NM_000546.5:c.319T>C
p.Tyr107His  ·  TP53
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Classification rationale
1

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.

clinvar ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

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.

PMID:12826609 ↗ PMID:30224644 ↗
4

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.

spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
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Gaps remaining
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Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This 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.
gnomAD v4.1This 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.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
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 ↗
Functional evidence
03
Functional
OncoKB: 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 ↗
In silico evidence
04
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 ↗
COSMIC evidence
05
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV53179040, n = 2 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant lies in a statistically significant hotspot.
ResidueY107
Hotspots ↗