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LYFE SCIENCES
Project: HERA
NM_007294.4:c.425C>A
p.Pro142His  ·  BRCA1
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Classification rationale
1

The BRCA1 c.425C>A (p.Pro142His) variant has been reported in ClinVar with an ENIGMA expert panel benign classification.

clinvar ↗
2

This variant is present in gnomAD, and the highest observed filter allele frequencies exceed the ENIGMA BS1_Strong threshold of 0.0001 (gnomAD v2.1 grpmax FAF 0.00015726; gnomAD v4.1 joint grpmax FAF 0.00015364).

cspec ↗ gnomad_v2 ↗ gnomad_v4 ↗
3

Calibrated BRCA1 functional evidence supports no damaging effect, with ENIGMA Table 9 assigning BS3_Strong and supplementary functional data describing no functional impact.

4

This missense change is outside the BRCA1 clinically important functional domains, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.00, which is consistent with BP1_Strong and does not support PP3.

cspec ↗ 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
  • —
Gaps remaining
  • —
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= 9.57746e-05; MAF= 0.00958%, 27/281912 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000283752; MAF= 0.02838%, 10/35242 alleles, homozygotes = 0); grpmax FAF= 0.00015726.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 5.63935e-05; MAF= 0.00564%, 91/1613662 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000250142; MAF= 0.02501%, 15/59966 alleles, homozygotes = 0); grpmax FAF= 0.00015364.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Benign (5 clinical laboratories) and as Likely benign (4 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as Benign by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Likely Neutral
OncoKB classifies this variant as Likely Neutral; biological effect: Likely Neutral.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV99070445, n = 1 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueP142
Hotspots ↗