NM_007294.3:c.4987-7A>G

BRCA1 · NP_009225.1:p.? · NM_007294.3

GRCh37: chr17:41219719 T>C · GRCh38: chr17:43067702 T>C

Gene: BRCA1 Transcript: NM_007294.3

Final call

PS3_Strong PM2_Supporting PP3_Supporting PP5_Supporting

Variant details

Gene

BRCA1

Transcript

NM_007294.3

Protein

NP_009225.1:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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

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.

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.

Final determination: One strong and at least two supporting pathogenic criteria meet the ENIGMA Table 3 rule for a Likely Pathogenic classification.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Not assessed	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. Available functional evidence supports a damaging splice effect, but the retrieved evidence does not provide a formal ENIGMA PVS1(RNA) strength assignment for this specific non-canonical intronic change.	cspec pvs1_gene_context pvs1_variant_assessment vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PS1	Not assessed	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.	cspec vcep_specifications_v1_2_2024_11_18
PS2	N/A	This criterion is not used in the ENIGMA BRCA1 specification.	cspec
PS3	Met	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.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 PMID:30209399
PS4	Not assessed	No case-control study or odds ratio data showing significantly increased prevalence in affected individuals were identified, so PS4 was not established.	cspec vcep_specifications_v1_2_2024_11_18
PM1	N/A	This criterion is not applicable for this BRCA1 intronic splice-region variant in the ENIGMA specification.	cspec
PM2	Met	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.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified for biallelic occurrence in a patient with BRCA1-related Fanconi anemia, so PM3 was not established.	cspec vcep_specifications_v1_2_2024_11_18
PM4	N/A	This criterion is not applicable because the variant is not an in-frame protein length change.	cspec
PM5	N/A	In the ENIGMA BRCA1 specification, PM5 is used for protein-terminating variants already annotated as PVS1. This intronic splice-region variant is not a protein-terminating variant in that framework context.	cspec vcep_specifications_table4_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PM6	N/A	This criterion is not used in the ENIGMA BRCA1 specification.	cspec
PP1	Not assessed	No quantitative segregation data were identified, so PP1 was not established.	cspec vcep_specifications_v1_2_2024_11_18
PP2	N/A	This criterion is not used in the ENIGMA BRCA1 specification.	cspec
PP3	Met	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.	cspec spliceai
PP4	Not assessed	No variant-specific clinical-history likelihood ratio meeting ENIGMA thresholds was identified, so PP4 was not established.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
PP5	Met	Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Likely pathogenic.	cspec clinvar
BA1	Not met	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%.	cspec gnomad_v2 gnomad_v4
BS1	Not met	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%.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No unaffected adult or recessive disease exclusion data meeting the BRCA1 ENIGMA point system were identified, so BS2 was not established.	cspec vcep_specifications_v1_2_2024_11_18
BS3	Not met	Available functional evidence does not support a benign effect. Instead, the retrieved calibrated functional data support a damaging splice-related loss-of-function effect.	vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 PMID:30209399
BS4	Not assessed	No quantitative lack-of-segregation evidence was identified, so BS4 was not established.	cspec vcep_specifications_v1_2_2024_11_18
BP1	N/A	This criterion is intended for silent, missense, or in-frame variants without predicted splice impact and does not apply to this intronic splice-region variant.	cspec
BP2	N/A	This criterion is not used in the ENIGMA BRCA1 specification.	cspec
BP3	N/A	This criterion is not used in the ENIGMA BRCA1 specification.	cspec
BP4	Not met	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. Available computational evidence therefore does not support a benign splicing prediction.	cspec spliceai
BP5	Not assessed	No variant-specific clinical-history likelihood ratio in the benign direction was identified, so BP5 was not established.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
BP6	N/A	This criterion is not used in the ENIGMA BRCA1 specification.	cspec
BP7	Not met	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. No benign RNA assay result was identified.	cspec spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.