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.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases and meeting ENIGMA PM2_Supporting.2 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.3 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 BP7.4
BRCA1
Final classification
Likely pathogenic
BRCA1 c.4987-7A>G · p.?
BRCA1
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.
Official ClinGen ENIGMA BRCA1/BRCA2 final-classification framework from Table 3 override in the CSPEC-derived final_classification_framework was applied.
Classification rationale
PS3PM2PP3PP5
Likely pathogenic
BRCA1 c.4987-7A>G
PS3 + PM2 + PP3 + PP5
→
Likely pathogenic
3
vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18PMID:30209399 ↗
Gene diagram
· NM_007294.3 · variants mapped to exon structure
BRCA1
NM_007294.3
Fetching transcript structure from UCSC…
Applied criteria · 4 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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).
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.65).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
PMID PMID:30209399
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
Sources & reference links