Variant classification summary

NM_007294.4:c.301+7G>A

BRCA1 · NP_009225.1:p.? · NM_007294.4

GRCh37: chr17:41256878 C>T · GRCh38: chr17:43104861 C>T

Gene: BRCA1 Transcript: NM_007294.4

Final call

Likely Benign

PP3 BS3 BP6

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA1 c.301+7G>A (NP_009225.1:p.?) variant has been reported in ClinVar, where the overall classification is Benign with expert panel review.

2

This variant is present in gnomAD, with AF 0.0000885 in v2.1 (25/282562 alleles; grpmax FAF 0.00010876) and AF 0.0000540 in v4.1 (87/1610834 alleles; grpmax FAF 0.00005311), so it is not absent from controls and does not meet BA1.

3

Well-established functional evidence supports no damaging effect: ENIGMA Table 9 assigns BS3 Strong based on no aberrant splicing in two studies and a calibrated study showing no functional impact.

4

In silico splicing prediction is conflicting with the functional evidence, because SpliceAI gives a maximum delta score of 0.29, which exceeds the ENIGMA PP3 threshold of 0.20 and argues against BP4.

Final determination: With conflicting evidence present, ENIGMA Table 3 directs use of the point-based framework; PP3_Supporting (+1), BS3_Strong (-4), and BP6_Supporting (-1) sum to -4 points, which falls in the Likely Benign range.

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	BRCA1 is a gene in which loss of function is an established disease mechanism, but this variant is an intronic +7 substitution rather than a nonsense, frameshift, or canonical ±1,2 splice-site variant. Available functional evidence shows no aberrant splicing and no functional impact, so PVS1 was not applied.	cspec pvs1_gene_context pvs1_variant_assessment vcep_specifications_table9_v1_2_2024_11_18
PS1	Not assessed	No evidence was identified showing that this variant has the same established pathogenic protein or splicing effect as a previously classified pathogenic or likely pathogenic BRCA1 variant, so PS1 was not assessed.	cspec
PS2	N/A	PS2 is not applicable under the BRCA1 ENIGMA specification for this review.	cspec
PS3	Not met	Available functional studies do not support a damaging effect. ENIGMA Table 9 summarizes this variant as showing no aberrant splicing in two studies and no functional impact in a calibrated study, so PS3 was not met.	vcep_specifications_table9_v1_2_2024_11_18 PMID:22505045 PMID:24667779
PS4	Not assessed	No case-control evidence was identified showing a statistically significant increase of this variant in affected individuals compared with controls, so PS4 was not assessed.	cspec clinvar
PM1	N/A	PM1 is not applicable under the BRCA1 ENIGMA specification for this intronic variant type.	cspec
PM2	Not met	This variant is not absent from population databases. It is present in gnomAD v2.1 at AF 0.0000885 (25/282562 alleles; grpmax FAF 0.00010876) and in gnomAD v4.1 at AF 0.0000540 (87/1610834 alleles; grpmax FAF 0.00005311), so the ENIGMA PM2 absence threshold is not met.	gnomad_v2 gnomad_v4 cspec
PM3	Not assessed	No evidence was identified for BRCA1-related Fanconi anemia with qualifying co-occurring variants in the same gene, so PM3 was not assessed.	cspec
PM4	N/A	PM4 is not applicable under the BRCA1 ENIGMA specification for this review.	cspec
PM5	N/A	Under the BRCA1 ENIGMA specification, PM5 is used for protein-termination-codon variants in eligible exons. This intronic +7 variant is not a protein-termination-codon variant, so PM5 is not applicable.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	PM6 is not applicable under the BRCA1 ENIGMA specification for this review.	cspec
PP1	Not assessed	No quantitative co-segregation data were identified for this variant, so PP1 was not assessed.	cspec
PP2	N/A	PP2 is not applicable under the BRCA1 ENIGMA specification for this review.	cspec
PP3	Met	SpliceAI predicts splice impact for this intronic variant, with a maximum delta score of 0.29. This is above the ENIGMA PP3 threshold of 0.20 for intronic variants outside the canonical ±1,2 splice sites, so PP3 is met at Supporting strength.	spliceai cspec
PP4	Not assessed	No calibrated multifactorial clinical-history likelihood ratio meeting ENIGMA PP4 thresholds was identified for this variant, so PP4 was not assessed.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
PP5	N/A	PP5 is not applicable under the BRCA1 ENIGMA specification for this review.	cspec
BA1	Not met	Population data do not reach the ENIGMA BA1 threshold. The observed grpmax FAF is 0.00010876 in gnomAD v2.1 and 0.00005311 in gnomAD v4.1, both below the BA1 cutoff of 0.001.	gnomad_v2 gnomad_v4 cspec
BS1	Not assessed	This variant is present in gnomAD, but the available summaries do not establish a non-founder population filter allele frequency that clearly exceeds the ENIGMA BS1 thresholds. BS1 was therefore not applied from the current evidence summary.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No evidence was identified showing qualifying observations in individuals without features of BRCA1-related Fanconi anemia under the ENIGMA point-based framework, so BS2 was not assessed.	cspec
BS3	Met	Well-established functional evidence supports no damaging effect. ENIGMA Table 9 assigns BS3 Strong for this intronic variant, citing no aberrant splicing in two studies and a calibrated study showing function similar to benign control variants with no functional impact.	vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 PMID:22505045 PMID:24667779
BS4	Not assessed	No quantitative lack-of-segregation data were identified for this variant, so BS4 was not assessed.	cspec
BP1	N/A	BP1 applies to silent, missense, or in-frame variants outside clinically important domains when no splicing effect is predicted. This intronic variant does not fit that rule, so BP1 is not applicable.	cspec
BP2	N/A	BP2 is not applicable under the BRCA1 ENIGMA specification for this review.	cspec
BP3	N/A	BP3 is not applicable under the BRCA1 ENIGMA specification for this review.	cspec
BP4	Not met	BP4 is not met because SpliceAI predicts splice impact, with a maximum delta score of 0.29. This is above the ENIGMA benign threshold of 0.10 for intronic variants outside the canonical splice sites.	spliceai cspec
BP5	Not assessed	No calibrated multifactorial clinical-history likelihood ratio meeting ENIGMA BP5 thresholds was identified for this variant, so BP5 was not assessed.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
BP6	Met	Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Benign.	cspec clinvar
BP7	Not met	This intronic +7 variant is in a position that can be considered for BP7, but BP7 Supporting requires BP4 and BP4 is not met because SpliceAI is 0.29, above the benign threshold of 0.10. The available non-damaging functional evidence is captured under BS3 rather than BP7.	cspec spliceai vcep_specifications_table9_v1_2_2024_11_18

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