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LYFE SCIENCES
Project: HERA
NM_007294.3:c.4987-7A>G
p.?  ·  BRCA1
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Classification rationale
1

The BRCA1 c.4987-7A>G (NP_009225.1:p.?) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar, including a ClinGen ENIGMA expert panel classification of likely pathogenic.

clinvar ↗
2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases and meeting ENIGMA PM2_Supporting.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

In a calibrated functional study incorporating mRNA splicing effects, this intronic variant showed complete functional impact/loss of function consistent with pathogenic control variants, and the ENIGMA BRCA1 specification assigns PS3 at strong strength for this exact variant.

PMID:30209399 ↗
4

SpliceAI predicts an abnormal splicing effect with a maximum delta score of 0.65, which is above the ENIGMA PP3 threshold of 0.2 and argues against BP4 or BP7.

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
—
—
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 (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory) and as Likely Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
ClinVar ↗
03
Functional
No functional summary recorded.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.65).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
06
Cancer hotspots
No cancer hotspot summary recorded.