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LYFE SCIENCES
Project: HERA
NM_007294.3:c.5200T>A
p.Phe1734Ile  ·  BRCA1
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Classification rationale
1

The BRCA1 c.5200T>A (p.Phe1734Ile; p.F1734I) variant has not been observed in COSMIC and has been reported in ClinVar, where the ClinGen ENIGMA BRCA1/2 expert panel classifies it as likely pathogenic.

clinvar ↗
2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity, although the ENIGMA PM2_Supporting rule was not formally established from the available depth-specific evidence.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

In a calibrated BRCA1 functional study, saturation genome editing showed loss of function similar to pathogenic control variants, and the ENIGMA BRCA1/2 specification assigns PS3 at Strong strength.

PMID:30209399 ↗
4

This missense change is located in the BRCA1 BRCT repeats; REVEL is 0.871, but under the ENIGMA computational rule the observed BayesDel score of 0.242362 and SpliceAI max delta score of 0.00 do not meet PP3 or BP4 thresholds.

spliceai ↗ cspec ↗
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
—
Research and evidence
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (3 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as Pathogenic (1 clinical laboratory) and as Likely Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 232047)
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. 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 = 0.871. BayesDel score = 0.242362.
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.
ResidueF1734
Hotspots ↗