Variant classification summary

NM_007294.3:c.301+7G>A

BRCA1 · NP_009225.1:p.? · NM_007294.3

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

Gene: BRCA1 Transcript: NM_007294.3

Final call

Likely Benign

PP3 BS3 BP6

Variant details

Gene

BRCA1

Transcript

NM_007294.3

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 and is classified there as Benign by the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel.

2

This variant is absent from gnomAD v2.1 but is present in gnomAD v4.1 at AF 5.40093e-05 (87/1610834 alleles; 0 homozygotes), so it is not absent from population controls.

3

Functional evidence supports a benign effect: ENIGMA BRCA1 Table 9 assigns BS3_Strong for this variant, and RNA studies reported no aberrant splicing.

4

Computational splicing evidence predicts possible splice impact, with a SpliceAI maximum delta score of 0.29, which meets the ENIGMA BRCA1 PP3 threshold and does not meet the BP4 threshold.

Final determination: With conflicting evidence, ENIGMA point-based combination applies: PP3_Supporting (+1), BS3_Strong (-4), and BP6_Supporting benign (-1) sum to -5 points, which falls in the Likely Benign range (-6 to -2).

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 BRCA1 variant is at c.301+7, outside the canonical donor ±1,2 positions used for default PVS1 application, and available RNA studies reported no aberrant splicing. Available evidence does not support a loss-of-function transcript for this variant, so PVS1 is not met.	cspec pvs1_gene_context pvs1_variant_assessment vcep_supplementarytables_v1_2_2024_11_18 PMID:22505045 PMID:24667779
PS1	Not assessed	No qualifying pathogenic reference variant with the same established splicing consequence was identified for this variant, so PS1 was not assessed.	cspec
PS2	N/A	This criterion is not used in the ENIGMA BRCA1 specification for BRCA1/2-related cancer interpretation.	cspec
PS3	Not met	Available functional evidence does not show a damaging effect. ENIGMA BRCA1 Table 9 instead records this variant as having function similar to benign control variants, and RNA studies reported no aberration.	vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 PMID:22505045 PMID:24667779
PS4	Not assessed	No case-control evidence showing significant enrichment in affected individuals was identified, so PS4 was not assessed.	cspec
PM1	N/A	PM1 is not applicable in the ENIGMA BRCA1 specification for this disease framework.	cspec
PM2	Not met	This variant is absent from gnomAD v2.1 but present in gnomAD v4.1 at AF 5.40093e-05 (87/1610834 alleles; 0 homozygotes) with grpmax FAF 5.311e-05, so it is not absent from population controls and PM2 is not met.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified for BRCA1-related Fanconi anemia with this variant observed in trans with another BRCA1 variant, so PM3 was not assessed.	cspec
PM4	N/A	PM4 is not applicable in the ENIGMA BRCA1 specification for this disease framework.	cspec
PM5	N/A	In the ENIGMA BRCA1 specification, PM5 is used for protein-terminating variants in eligible exons or for qualifying missense/splice comparators, and this c.301+7G>A intronic variant does not meet those use conditions.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	This criterion is not used in the ENIGMA BRCA1 specification for BRCA1/2-related cancer interpretation.	cspec
PP1	Not assessed	No quantitative segregation data were identified for this variant, so PP1 was not assessed.	cspec
PP2	N/A	PP2 is not applicable in the ENIGMA BRCA1 specification for this disease framework.	cspec
PP3	Met	SpliceAI predicts splice impact with a maximum delta score of 0.29, which is above the ENIGMA BRCA1 PP3 threshold of 0.2 for intronic variants outside the ±1,2 splice positions. This supports PP3 at supporting strength.	cspec spliceai
PP4	Not assessed	No exact variant-level clinical-history likelihood ratio meeting ENIGMA BRCA1 PP4 thresholds was identified, so PP4 was not assessed.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
PP5	N/A	PP5 is not used in this ENIGMA BRCA1 framework.	cspec
BA1	Not met	The observed gnomAD v4.1 grpmax FAF is 5.311e-05, which is below the ENIGMA BRCA1 BA1 threshold of 0.001. BA1 is not met.	cspec gnomad_v4
BS1	Not assessed	Available population data show that this variant is present at low frequency in gnomAD v4.1, but the reviewed evidence did not establish a clearly qualifying non-founder filter allele frequency for separate BS1 application under the ENIGMA BRCA1 population framework.	cspec gnomad_v4
BS2	Not assessed	No data were identified showing this variant in individuals without features of BRCA1-related Fanconi anemia at the point thresholds required for BS2, so BS2 was not assessed.	cspec
BS3	Met	ENIGMA BRCA1 Table 9 assigns BS3 at strong strength for this variant. A calibrated functional study found function similar to benign control variants, and two RNA studies reported no aberrant splicing, supporting no damaging functional effect.	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 in ENIGMA BRCA1 is used for silent, missense, or in-frame variants without predicted splice impact, and this variant is intronic.	cspec
BP2	N/A	BP2 is not applicable in the ENIGMA BRCA1 specification for this disease framework.	cspec
BP3	N/A	BP3 is not applicable in the ENIGMA BRCA1 specification for this disease framework.	cspec
BP4	Not met	For intronic variants outside the native donor and acceptor ±1,2 positions, ENIGMA BRCA1 requires SpliceAI 0.1 or less for BP4. This variant has a maximum SpliceAI delta score of 0.29, which is above that threshold, so BP4 is not met.	cspec spliceai
BP5	Not assessed	No exact variant-level clinical-history likelihood ratio meeting ENIGMA BRCA1 BP5 thresholds was identified, 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 assessed	This variant is at +7, a position that can enter the ENIGMA BRCA1 BP7 framework, but BP4 is not met because SpliceAI is 0.29. RNA studies reported no aberration, and this benign functional evidence is already captured by BS3_Strong, so BP7 was not separately applied.	cspec spliceai vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 PMID:22505045 PMID:24667779

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