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
Final classification
Likely pathogenic
PS3PM2PP3PP5
BRCA1
c.4987-7A>G
p.?
This variant
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 ↗
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may be applied incorrectly, sources may be misread, and a confident-looking
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its underlying evidence before relying on any call.
Gene diagram
· NM_007294.3 · variants mapped to exon structure
BRCA1
NM_007294.3
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 14 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
PS3
strong
review
Pathogenic
In a calibrated functional study that incorporated mRNA splicing effects, this intronic variant showed complete functional impact/loss of function and protein function similar to pathogenic control variants, supporting a damaging effect. The ENIGMA BRCA1 specification lists this exact variant as PS3 at strong strength.
Specifications Table 9 lists BRCA1 c.4987-7A>G as PS3 Strong.Supplementary Table 4 records BRCA1 c.4987-7A>G as Functional impact - complete / LOF.The cited calibrated study is Findlay 2018.
PM2
supporting
review
Pathogenic
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports rarity in population databases and meets the ENIGMA PM2_Supporting rule.
Absent from gnomAD v2.1.Absent from gnomAD v4.1.
PP3
supporting
review
Pathogenic
SpliceAI predicts a splice effect with a maximum delta score of 0.65, which is above the ENIGMA PP3 threshold of 0.2 for intronic variants outside the donor and acceptor +/-1,2 positions. This supports a predicted abnormal splicing effect.
SpliceAI DS_AL 0.65max delta score 0.65.Variant position is c.4987-7
Assessed · not applied
· 5 not met · 9 not assessed
Pathogenic
PVS1
This intronic variant is outside the canonical +/-1,2 splice consensus positions, and the generic PVS1 scaffold does not place it in a default null-variant category.
PS1
No directly comparable pathogenic or likely pathogenic variant with the same demonstrated splicing consequence was identified in the retrieved evidence, so PS1 was not established.
PS4
No case-control study or odds ratio data showing significantly increased prevalence in affected individuals were identified, so PS4 was not established.
PM3
No evidence was identified for biallelic occurrence in a patient with BRCA1-related Fanconi anemia, so PM3 was not established.
PP1
No quantitative segregation data were identified, so PP1 was not established.
PP4
No variant-specific clinical-history likelihood ratio meeting ENIGMA thresholds was identified, so PP4 was not established.
Benign
BA1
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it does not meet the ENIGMA BA1 threshold of filter allele frequency greater than 0.1%.
BS1
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so it does not meet the ENIGMA BS1 thresholds of filter allele frequency above 0.002% or 0.01%.
BS2
No unaffected adult or recessive disease exclusion data meeting the BRCA1 ENIGMA point system were identified, so BS2 was not established.
BS3
Available functional evidence does not support a benign effect.
BS4
No quantitative lack-of-segregation evidence was identified, so BS4 was not established.
BP4
SpliceAI predicts a splice effect with a maximum delta score of 0.65, which is above the ENIGMA BP4 threshold of 0.1 for intronic variants outside the canonical splice sites.
BP5
No variant-specific clinical-history likelihood ratio in the benign direction was identified, so BP5 was not established.
BP7
This intronic variant is at position -7, which is not in the ENIGMA BP7 supporting zone for intronic variants at or beyond -21/+7, and computational evidence predicts splice disruption rather than no impact.
N/A · 10
PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · BP1 · BP2 · BP3 · BP6
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.
Accurate classification of BRCA1 variants with saturation genome editing.
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
strong
Sources & reference links