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LYFE SCIENCES
Project: HERA
NM_007294.3:c.101C>T
p.Pro34Leu  ·  BRCA1
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Classification rationale
1

The BRCA1 c.101C>T (p.Pro34Leu) variant has not been observed in COSMIC and has been reported in ClinVar, where the ClinGen ENIGMA expert panel classified it as Likely Pathogenic.

clinvar ↗
2

This variant is absent from gnomAD v2.1 and is present at very low frequency in gnomAD v4.1 (5/1,613,658 alleles; AF 3.10e-06; grpmax FAF 1.24e-06).

gnomad_v2 ↗ gnomad_v4 ↗
3

In a calibrated BRCA1 functional study summarized by the ENIGMA BRCA1 specification, c.101C>T (p.Pro34Leu) showed loss of function/complete functional impact, supporting PS3_Strong.

PMID:30209399 ↗
4

This missense change is located in the BRCA1 RING domain; BayesDel is 0.450189, above the ENIGMA PP3 threshold of 0.28, REVEL is 0.837, and SpliceAI predicts no significant splice impact with a max delta score of 0.01, supporting a damaging protein effect without predicted splice disruption.

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 v2.1Absent from gnomAD v2.1.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 3.09855e-06; MAF= 0.00031%, 5/1613658 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.23801e-06; MAF= 0.00042%, 5/1179798 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as Likely Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA1, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.837. BayesDel score = 0.450189.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueP34
Hotspots ↗