Variant classification summary

NM_000059.4:c.7976+24G>A

BRCA2 · NP_000050.3:p.? · NM_000059.4

GRCh37: chr13:32936854 G>A · GRCh38: chr13:32362717 G>A

Gene: BRCA2 Transcript: NM_000059.4

Final call

Likely Benign

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.?

gnomAD AF

5.829464594684769e-05 (v4.1)

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA2 NM_000059.4:c.7976+24G>A (NP_000050.3:p.?) variant has been reported in ClinVar (Variation ID 371868), although submission-level classification details were not available in the reviewed record.

2

This variant is present in population databases, including gnomAD v2.1 at 12/250842 alleles with an East Asian grpmax filter allele frequency of 0.00037674 and gnomAD v4.1 at 94/1612498 alleles; the gnomAD v2.1 frequency exceeds the ENIGMA BRCA2 BS1 strong threshold of 0.0001.

3

In silico splicing prediction does not support an abnormal splicing effect, with a SpliceAI maximum delta score of 0.00, consistent with BP4 and BP7 and arguing against PP3.

Final determination: Likely benign based on one strong benign criterion (BS1) and two supporting benign criteria (BP4, BP7) under the ENIGMA BRCA1/BRCA2 Table 3 combination rules.

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 c.7976+24, outside the canonical +/-1,2 splice consensus positions and outside the default null-variant categories used for PVS1. No variant-specific RNA study showing a damaging transcript effect was identified, so PVS1 is not met.	cspec pvs1_gene_context pvs1_variant_assessment spliceai
PS1	Not assessed	No confirmed pathogenic or likely pathogenic comparator with the same demonstrated splicing effect was identified, so PS1 was not assessed.	cspec spliceai
PS2	N/A	This criterion is not used in the BRCA2 ENIGMA specification.	cspec
PS3	Not assessed	No calibrated functional assay result for this specific variant was identified in the reviewed BRCA2 functional evidence sources, so PS3 was not assessed.	cspec vcep_specifications_table9_v1_2_2024_11_18
PS4	Not assessed	No case-control study or quantitative enrichment data showing a significant excess of this variant in affected individuals were identified, so PS4 was not assessed.	cspec vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
PM1	N/A	This criterion is not applied independently in the BRCA2 ENIGMA specification and is handled through the bioinformatic framework for other variant classes.	cspec
PM2	Not met	This variant is present in gnomAD rather than absent from controls. In gnomAD v2.1 it is seen in 12/250842 alleles, so PM2 is not met.	cspec gnomad_v2
PM3	Not assessed	No evidence was identified that this variant occurred in trans with another BRCA2 pathogenic variant in an individual with a phenotype consistent with BRCA2-related Fanconi anemia, so PM3 was not assessed.	cspec
PM4	N/A	This criterion is not used in the BRCA2 ENIGMA specification.	cspec
PM5	N/A	In the BRCA2 ENIGMA framework, PM5 is repurposed for protein-truncating variants in eligible exons. This intronic non-truncating variant does not meet that use case, so PM5 is not applicable.	cspec pm5_candidates
PM6	N/A	This criterion is not used in the BRCA2 ENIGMA specification.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 was not assessed.	cspec
PP2	N/A	This criterion is not used in the BRCA2 ENIGMA specification.	cspec
PP3	Not met	Available computational evidence does not support a splice-altering effect. SpliceAI shows a maximum delta score of 0.00, which is below the ENIGMA BRCA2 PP3 threshold of >=0.20, so PP3 is not met.	cspec spliceai
PP4	Not assessed	No variant-specific clinical-history likelihood-ratio entry was identified in the reviewed BRCA2 ENIGMA clinical-history resource, so PP4 was not assessed.	cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
PP5	N/A	This criterion is not for use in the BRCA2 ENIGMA specification.	cspec
BA1	Not met	The ENIGMA BRCA2 BA1 threshold is a non-founder population filter allele frequency greater than 0.001 in gnomAD v2.1 and/or v3.1. The observed gnomAD v2.1 grpmax FAF is 0.00037674, which is below 0.001, so BA1 is not met.	cspec gnomad_v2 gnomad_v4
BS1	Met	This variant is present in gnomAD v2.1 with a highest non-founder population filter allele frequency of 0.00037674 in East Asian samples, which is above the ENIGMA BRCA2 BS1 strong threshold of 0.0001. This supports BS1 at strong strength.	cspec gnomad_v2
BS2	Not assessed	No qualifying observations in individuals lacking features of BRCA2-related Fanconi anemia were identified for this variant, so BS2 was not assessed.	cspec
BS3	Not assessed	No calibrated functional assay showing no damaging effect for this specific variant was identified in the reviewed BRCA2 functional evidence sources, so BS3 was not assessed.	cspec vcep_specifications_table9_v1_2_2024_11_18
BS4	Not assessed	No quantitative lack-of-segregation data were identified for this variant, so BS4 was not assessed.	cspec vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
BP1	N/A	BP1 in the BRCA2 ENIGMA specification applies to silent, missense, or in-frame variants outside clinically important domains with no predicted splice impact. This intronic variant is not in that variant class, so BP1 is not applicable.	cspec spliceai
BP2	N/A	This criterion is not used in the BRCA2 ENIGMA specification.	cspec
BP3	N/A	This criterion is not used in the BRCA2 ENIGMA specification.	cspec
BP4	Met	This intronic variant lies outside the native donor and acceptor +/-1,2 splice sites, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, which is below the ENIGMA BRCA2 BP4 threshold of <=0.10. This supports BP4 at supporting strength.	cspec spliceai
BP5	Not assessed	No variant-specific clinical-history likelihood-ratio entry supporting a benign direction was identified in the reviewed BRCA2 ENIGMA clinical-history resource, so BP5 was not assessed.	cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
BP6	N/A	This criterion is not used in the BRCA2 ENIGMA specification.	cspec
BP7	Met	This intronic variant is located at +24, which is beyond the conserved donor motif position +7 used in the ENIGMA BRCA2 BP7 rule, and BP4 is met because SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. This supports BP7 at supporting strength.	cspec spliceai

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