LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-05-28
Case ID: NM_000059.4_c.9257-18C_A_20260528_144344
Framework: ACMG/AMP 2015 with ENIGMA Table 3 adaptations
Variant classification summary

BRCA2  · NP_000050.3:p.?  · NM_000059.4
GRCh37: chr13:32968808 C>A  ·  GRCh38: chr13:32394671 C>A
Gene: BRCA2 Transcript: NM_000059.4
Final call
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRCA2
Transcript
NM_000059.4
Protein
NP_000050.3:p.?
gnomAD AF
6.220754677074404e-06 (v4.1)
ClinVar
Likely benign
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
The BRCA2 c.9257-18C>A variant has been reported in ClinVar, where most clinical laboratory submissions classify it as likely benign or benign, although one submission remains uncertain.
2
This variant is present at very low frequency in population databases, with 3/240598 alleles in gnomAD v2.1 and 10/1607522 alleles in gnomAD v4.1; these frequencies are below the BS1 and BA1 thresholds but do not meet the PM2 absence requirement.
3
In a published RNA study, RT-PCR showed no aberrant splicing for this variant, and the BRCA multifactorial splicing dataset also records no aberration, which is consistent with no measurable splice disruption.
4
Computational splicing prediction supports a benign interpretation, with SpliceAI showing a maximum delta score of 0.01, below the BRCA2 BP4 threshold of 0.1 and well below the PP3 threshold of 0.2.
Final determination:
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.9257-18, outside the canonical ±1,2 splice consensus positions used for BRCA2 PVS1 null-variant application, and SpliceAI does not predict a splice-disrupting effect (max delta score 0.01). Available evidence does not support a loss-of-function mechanism for this variant.
cspec pvs1_gene_context pvs1_variant_assessment spliceai
PS1 Not assessed No published comparator variant with the same proven splicing effect was identified to support PS1 for this intronic BRCA2 variant.
cspec
PS2 N/A De novo occurrence is not a criterion used in this BRCA2 VCEP framework.
cspec
PS3 N/A For BRCA2 intronic variants, RNA-only evidence is interpreted under PVS1 or BP7 rather than PS3. No protein-based functional study supporting a damaging effect was identified for this variant.
cspec vcep_specifications_v1_2_2024_11_18
PS4 Not assessed No case-control study showing significant enrichment of this variant in affected individuals compared with controls was identified.
cspec clinvar
PM1 N/A PM1 is not used as an independent criterion in this BRCA2 VCEP framework and is captured within the bioinformatic/domain rules for PP3 and BP4.
cspec
PM2 Not met This variant is not absent from population databases. It is present in gnomAD v2.1 at 3/240598 alleles (AF 0.00125%) and in gnomAD v4.1 at 10/1607522 alleles (AF 0.00062%), so the BRCA2 PM2 absence requirement is not met.
cspec gnomad_v2 gnomad_v4
PM3 Not assessed No evidence was identified that this variant was observed in trans with a pathogenic BRCA2 variant in an individual with BRCA2-related Fanconi anemia features.
cspec
PM4 N/A PM4 is not applicable for this BRCA2 VCEP framework.
cspec
PM5 N/A In this BRCA2 VCEP, PM5 is repurposed for protein-truncating variant logic rather than classic same-residue missense comparison, and this intronic non-truncating variant does not fall in that PM5 category.
cspec pm5_candidates
PM6 N/A PM6 is not a criterion used in this BRCA2 VCEP framework.
cspec
PP1 Not assessed No quantitative segregation data were identified for this variant.
cspec
PP2 N/A PP2 is not a criterion used in this BRCA2 VCEP framework.
cspec
PP3 Not met Computational evidence does not support a splice-altering effect. SpliceAI shows a maximum delta score of 0.01, which is below the BRCA2 PP3 threshold of 0.2.
cspec spliceai
PP4 Not assessed No qualifying BRCA2 clinical-history likelihood ratio from the ENIGMA-approved LR resource was identified for this variant.
cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
PP5 N/A PP5 is not used in this VCEP framework.
cspec
BA1 Not met Population frequency is well below the BRCA2 BA1 threshold. The highest observed filter allele frequency is 7.41e-06 in gnomAD v2.1 and 3.68e-06 in gnomAD v4.1, both below the BA1 threshold of 0.001.
cspec gnomad_v2 gnomad_v4
BS1 Not met Population frequency is below the BRCA2 BS1 threshold. The highest observed filter allele frequency is 7.41e-06 in gnomAD v2.1 and 3.68e-06 in gnomAD v4.1, both below the supporting threshold of 0.00002.
cspec gnomad_v2 gnomad_v4
BS2 Not assessed No data were identified showing this variant in a context that would score BS2 under the BRCA2 Fanconi anemia framework.
cspec
BS3 N/A For this intronic variant, RNA-only evidence is interpreted under BP7 rather than BS3. No protein-based functional study showing no damaging effect was identified.
cspec vcep_specifications_v1_2_2024_11_18
BS4 Not assessed No quantitative non-segregation data were identified for this variant.
cspec
BP1 N/A BP1 in this BRCA2 VCEP applies to silent, missense, or in-frame variants outside key domains with no splice impact, and does not apply to an intronic variant.
cspec
BP2 N/A BP2 is not a criterion used in this BRCA2 VCEP framework.
cspec
BP3 N/A BP3 is not applicable in this BRCA2 VCEP framework.
cspec
BP4 Met This intronic variant is outside the native donor and acceptor splice sites and SpliceAI predicts no significant splice impact, with a maximum delta score of 0.01, which is below the BRCA2 BP4 threshold of 0.1. This supports a benign computational interpretation.
cspec spliceai
BP5 Not assessed No qualifying BRCA2 clinical-history likelihood ratio against pathogenicity was identified for this variant in the ENIGMA-approved LR resource.
cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
BP6 N/A BP6 is not a criterion used in this BRCA2 VCEP framework.
cspec
BP7 Not met A published RT-PCR study reported no aberrant splicing for this variant, and the multifactorial splicing dataset also lists no aberration; however, the variant is at c.9257-18, which is not in the intronic position range automatically eligible for BP7 from BP4 alone under the BRCA2 rule, and no explicit ENIGMA BP7 RNA calibration assignment was retrieved for this exact variant. BP7 is therefore not applied at this stage.
cspec spliceai vcep_humu_40_1557_s001 PMID:16619214
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