Variant classification summary

NM_007294.4:c.80+5G>C

BRCA1 · NP_009225.1:p.? · NM_007294.4

GRCh37: chr17:41276029 C>G · GRCh38: chr17:43124012 C>G

Gene: BRCA1 Transcript: NM_007294.4

Final call

BP4_Supporting

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.?

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA1 c.80+5G>C (NP_009225.1:p.?) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as a variant of uncertain significance without expert panel review.

2

This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, which supports rarity in population databases.

3

SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, which is below the BRCA1 PP3 threshold of 0.2 and within the BP4 no-splice-impact threshold of 0.1 for intronic variants outside the native donor ±1,2 positions.

Final determination: BP4_Supporting alone does not meet ENIGMA Table 3 thresholds for likely benign or benign classification; therefore the classification is Uncertain Significance.

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 met	This intronic variant is at donor position +5, not at the canonical ±1,2 splice site positions used for BRCA1 PVS1 application, and no variant-specific RNA study showing an abnormal transcript with loss-of-function consequence was identified. Available evidence therefore does not support applying PVS1 for this variant at this time.	cspec pvs1_gene_context pvs1_variant_assessment vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PS1	Not met	No previously classified pathogenic or likely pathogenic variant with the same demonstrated splice effect as this variant was identified. A different BRCA1 change at the same +5 position has published splice evidence, but that is not sufficient to show that c.80+5G>C has the same splice consequence.	cspec vcep_specifications_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PS2	N/A	This criterion is not applicable in the BRCA1 ENIGMA specification.	cspec
PS3	Not assessed	No calibrated functional study for c.80+5G>C was identified in the reviewed BRCA1 functional tables. Published functional evidence was found for nearby splice-site variants, but not for this exact nucleotide change.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PS4	Not assessed	No case-control or statistically enriched affected-individual data were identified for this variant. The available ClinVar record does not provide evidence meeting the BRCA1 PS4 threshold.	clinvar cspec vcep_specifications_v1_2_2024_11_18
PM1	N/A	This criterion is not applicable in the BRCA1 ENIGMA specification because domain-based evidence is incorporated through other rules rather than used as a separate PM1 code.	cspec vcep_specifications_v1_2_2024_11_18
PM2	Not assessed	This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, supporting rarity. However, BRCA1 ENIGMA PM2_Supporting requires absence from gnomAD v2.1 and v3.1 with adequate regional read depth, and the needed v3.1/depth documentation was not directly available here.	gnomad_v2 gnomad_v4 gnomad_canada cspec vcep_specifications_v1_2_2024_11_18
PM3	Not assessed	No evidence was identified that this variant has been observed in trans with another BRCA1 pathogenic variant in a person with BRCA1-related Fanconi anemia. Available data do not support PM3 assessment.	cspec vcep_specifications_v1_2_2024_11_18
PM4	N/A	This criterion is not applicable in the BRCA1 ENIGMA specification.	cspec
PM5	N/A	For BRCA1, PM5 is repurposed for protein-truncating variants already annotated as PVS1. This intronic splice-region variant is not eligible for that PM5 framework.	pm5_candidates cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	This criterion is not applicable in the BRCA1 ENIGMA specification.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 cannot be assessed.	cspec vcep_specifications_v1_2_2024_11_18
PP2	N/A	This criterion is not applicable in the BRCA1 ENIGMA specification.	cspec
PP3	Not met	SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.00. This is below the BRCA1 PP3 threshold of 0.2, so computational evidence does not support a predicted splice-disrupting effect.	spliceai cspec vcep_specifications_v1_2_2024_11_18
PP4	Not assessed	No exact clinical-history likelihood-ratio entry for c.80+5G>C was identified in the reviewed BRCA1 clinical-history dataset, so PP4 cannot be assessed from the available evidence.	cspec vcep_pmid_31853058_brca1_clinical_history_lr vcep_pmid_31853058_li_2020_geneticsinmedicine
PP5	N/A	This criterion is not for use in the BRCA1 ENIGMA specification.	cspec
BA1	Not met	This variant is absent from the reviewed population datasets and therefore is well below the BRCA1 BA1 threshold of filter allele frequency greater than 0.1%. BA1 is not met.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS1	Not met	This variant is absent from the reviewed population datasets and therefore is below the BRCA1 BS1 thresholds of filter allele frequency greater than 0.002% or 0.01%. BS1 is not met.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS2	Not assessed	No point-based evidence was identified showing this variant in individuals without features of BRCA1-related Fanconi anemia as required by the BRCA1 ENIGMA framework. BS2 cannot be assessed from the available evidence.	cspec vcep_specifications_v1_2_2024_11_18
BS3	Not assessed	No well-established functional study showing normal splicing or normal BRCA1 function for c.80+5G>C was identified. BS3 cannot be assessed from the available evidence.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
BS4	Not assessed	No lack-of-segregation data were identified for this variant, so BS4 cannot be assessed.	cspec vcep_specifications_v1_2_2024_11_18
BP1	N/A	BP1 in the BRCA1 ENIGMA specification applies to silent, missense, or in-frame coding variants outside clinically important domains with no predicted splice impact. This intronic variant is not eligible.	cspec vcep_specifications_v1_2_2024_11_18
BP2	N/A	This criterion is not applicable in the BRCA1 ENIGMA specification.	cspec
BP3	N/A	This criterion is not applicable in the BRCA1 ENIGMA specification.	cspec
BP4	Met	This intronic variant lies outside the native donor ±1,2 splice positions, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.00. This is below the BRCA1 BP4 threshold of 0.1 for no predicted splice impact, so BP4 is met at Supporting strength.	spliceai cspec vcep_specifications_v1_2_2024_11_18
BP5	Not assessed	No exact clinical-history likelihood-ratio entry for c.80+5G>C was identified in the reviewed BRCA1 clinical-history dataset, so BP5 cannot be assessed from the available evidence.	cspec vcep_pmid_31853058_brca1_clinical_history_lr vcep_pmid_31853058_li_2020_geneticsinmedicine
BP6	N/A	This criterion is not for use in the BRCA1 ENIGMA specification.	cspec
BP7	Not met	SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, but BRCA1 BP7_Supporting for intronic variants is limited to positions at or beyond +7 or -21 when BP4 is met. This variant is at +5, so BP7 is not met, and no RNA study showing normal splicing was identified for BP7_Strong.	spliceai cspec vcep_specifications_v1_2_2024_11_18

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.