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LYFE SCIENCES
Project: HERA
NM_007294.3:c.4159T>C
p.Ser1387Pro  ·  BRCA1
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Classification rationale
1

The BRCA1 c.4159T>C (p.Ser1387Pro) variant has been reported in ClinVar, where the ClinGen ENIGMA BRCA1/2 expert panel classifies it as Likely Benign despite conflicting individual submissions.

clinvar ↗
2

This variant is present at very low frequency in population databases, including gnomAD v2.1 at 1/248290 alleles (AF 0.00040%) and gnomAD v4.1 at 2/1612348 alleles (AF 0.00012%; grpmax FAF 2.8e-07), which is too low for BA1 or BS1 and means PM2 is not met because the variant is not absent from controls.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

No exact curated functional assay result for p.(Ser1387Pro) was identified in the ENIGMA BRCA1 functional tables, so PS3 and BS3 were not applied from the available functional evidence.

4

In silico data support a benign interpretation under the ENIGMA BRCA1 framework because p.(Ser1387Pro) lies outside the BRCA1 clinically important domains, SpliceAI predicts no splice impact (max delta 0.00), and the missense change therefore meets BP1_Strong; BayesDel is 0.148379 and PP3 is not met.

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= 4.02755e-06; MAF= 0.00040%, 1/248290 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.89696e-06; MAF= 0.00089%, 1/112398 alleles, homozygotes = 0).
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 1.24043e-06; MAF= 0.00012%, 2/1612348 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69594e-06; MAF= 0.00017%, 2/1179284 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as Uncertain Significance (1 clinical laboratory) and as Likely benign (1 clinical laboratory) and as Likely Benign 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 = 0.00). REVEL score = 0.481. BayesDel score = 0.148379.
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.
ResidueS1387
Hotspots ↗