Variant classification summary

NM_000059.4:c.1909+11_1909+12del

BRCA2 · NP_000050.3:p.? · NM_000059.4

GRCh37: chr13:32907533 GTC>G · GRCh38: chr13:32333396 GTC>G

Gene: BRCA2 Transcript: NM_000059.4

Final call

Likely Benign

BP4 supporting BP7 supporting

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000059.4:c.1909+11_1909+12del is an intronic deletion at positions +11 and +12 of intron 10, outside the native donor splice consensus (+/-1,2). SpliceAI predicts no splicing impact (max delta = 0.00). BP4_Supporting is met per ENIGMA BRCA2 specification Figure 1A.

2

The variant is located at intronic position +11, outside the conserved donor motif (beyond +7). BP4 is met (SpliceAI ≤0.1). BP7_Supporting is met per ENIGMA BRCA2 specification Figure 1A and Appendix J.

3

No pathogenic criteria are met. PVS1 is not met (outside canonical +/-1,2 splice consensus; does not qualify as a null variant per ENIGMA PVS1 criteria). PM2 is explicitly not applicable for deletion variants per ENIGMA specification. PP3 is not met (SpliceAI max delta = 0.00 < 0.2). Two supporting benign criteria are met (BP4_Supporting, BP7_Supporting). Per ENIGMA Table 3 combining rules, ≥2 Supporting (Benign) criteria supports classification as Likely Benign.

Final determination: Per ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3, >=2 Supporting (Benign) criteria without any pathogenic criteria met results in a Likely Benign classification.

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	NM_000059.4:c.1909+11_1909+12del is an intronic deletion at positions +11 and +12 of intron 10, outside the canonical donor splice consensus (+/-1,2). Does not meet ENIGMA PVS1 null-variant criteria (nonsense, frameshift, canonical +/-1,2 splice, initiation codon, or exon-level deletion).	cspec
PS1	Not met	SpliceAI predicts no splicing impact (max delta = 0.00). No previously classified pathogenic variant with the same predicted splicing effect available as comparator. PS1 is not met.	spliceai cspec
PS2	N/A	PS2 is not applicable for this VCEP per ClinGen ENIGMA BRCA1/2 specification v1.2.	cspec
PS3	Not assessed	No functional assay data available for this intronic deletion variant in ENIGMA Specifications Table 9 or published literature.
PS4	Not assessed	Variant is absent from ClinVar and COSMIC. No case-control study data available for prevalence comparison per ENIGMA PS4 specification.	clinvar
PS5	N/A	PS5 is not applicable for this VCEP per ClinGen recommendations.	cspec
PM1	N/A	PM1 is not applicable for this VCEP; captured by bioinformatic analysis (PP3/BP4) per ENIGMA BRCA2 specification.	cspec
PM2	N/A	PM2 is not applicable for deletion variants per ENIGMA BRCA2 specification v1.2: 'Do not apply for insertion, deletion or delins variants.'	cspec
PM4	N/A	PM4 is not applicable for this VCEP per ENIGMA BRCA1/2 specification v1.2.	cspec
PM5	N/A	PM5 in ENIGMA BRCA2 is repurposed for PTC comparator logic (PM5_PTC). This intronic deletion at +11/+12 is not a protein termination codon variant and is not located in an exon.	cspec
PM6	N/A	PM6 is not applicable for this VCEP per ENIGMA BRCA1/2 specification v1.2.	cspec
PP1	Not assessed	No co-segregation data available for quantitative analysis per ENIGMA PP1 specification.
PP2	N/A	PP2 is not applicable for this VCEP per ENIGMA BRCA1/2 specification v1.2.	cspec
PP3	Not met	SpliceAI predicts no significant splice impact (max delta = 0.00), well below the ENIGMA PP3 threshold of SpliceAI ≥0.2 for intronic variants outside donor/acceptor +/-1,2 sites.	spliceai cspec
PP4	Not assessed	Variant is not listed in the Li et al. 2020 (PMID:31853058) BRCA2 clinical-history likelihood-ratio table. No clinical-history LR data available for PP4 assessment.	PMID:31853058
PP5	N/A	PP5 is not applicable for this VCEP per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.	cspec
BA1	Not met	Variant is absent from gnomAD v2.1 and v4.1. BA1 threshold (FAF > 0.1% in non-founder populations) is not met.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	Variant is absent from gnomAD v2.1 and v4.1. Does not meet ENIGMA BS1 thresholds (FAF > 0.00002 for Supporting; FAF > 0.0001 for Strong).	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No proband-level data available to evaluate for BS2 points under ENIGMA Specifications Table 8 (absence of Fanconi Anemia phenotype).
BS3	Not assessed	No functional assay data available for this intronic deletion variant in ENIGMA Specifications Table 9 or published literature.
BS4	Not assessed	No segregation data available for quantitative BS4 likelihood-ratio analysis per ENIGMA specification.
BP1	N/A	BP1 applies to coding-region variants (silent, missense, in-frame indels). This is an intronic deletion at +11/+12, outside the coding region.	cspec
BP2	N/A	BP2 is not applicable for this VCEP per ENIGMA BRCA1/2 specification v1.2.	cspec
BP3	N/A	BP3 is not applicable for this VCEP; captured by bioinformatic tool prediction and domain analysis per ENIGMA specification.	cspec
BP4	Met	NM_000059.4:c.1909+11_1909+12del is an intronic deletion at positions +11 and +12 of intron 10, outside the native donor splice consensus (+/-1,2). SpliceAI predicts no splicing impact (max delta = 0.00, ≤0.1). BP4_Supporting is met per ENIGMA BRCA2 specification Figure 1A.	spliceai cspec
BP5	Not assessed	Variant is not listed in the Li et al. 2020 (PMID:31853058) BRCA2 clinical-history likelihood-ratio table. No clinical-history LR data available for BP5 assessment.	PMID:31853058
BP6	N/A	BP6 is not applicable for this VCEP per ENIGMA BRCA1/2 specification v1.2.	cspec
BP7	Met	The intronic deletion is located at position +11, outside the conserved donor motif (beyond +7). BP4 is met (SpliceAI max delta = 0.00 ≤ 0.1). BP7_Supporting is met per ENIGMA BRCA2 specification Figure 1A and Appendix J.	spliceai cspec

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