Variant classification summary

NM_000059.3:c.68-7del

BRCA2 · NP_000050.2:p.? · NM_000059.3

GRCh37: chr13:32893197 AT>A · GRCh38: chr13:32319060 AT>A

Gene: BRCA2 Transcript: NM_000059.3

Final call

Benign

BA1 BS1 BP4 BP6

Variant details

Gene

BRCA2

Transcript

NM_000059.3

Protein

NP_000050.2:p.?

gnomAD AF

0.0002616769332743014 (v4.1)

ClinVar

Benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA2 c.68-7del (p.?) variant has been reported in ClinVar and is classified as Benign by the ClinGen ENIGMA BRCA1 and BRCA2 expert panel, although some ClinVar submissions remain uncertain significance.

2

This variant is present in gnomAD, and in gnomAD v2.1 the grpmax filter allele frequency is 0.00155833, which is above the ENIGMA BRCA2 BA1 threshold of 0.001 and the BS1 strong threshold of 0.0001.

3

Computational splicing evidence does not support a deleterious effect because SpliceAI predicts a maximum delta score of 0.04, which is below the BRCA2 BP4 threshold of 0.1 and below the PP3 threshold of 0.2.

Final determination: Benign based on BA1 stand-alone benign; additional benign evidence includes BS1 and BP4/BP6 supporting benign criteria.

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	BRCA2 loss of function is an established disease mechanism in this framework, but this intronic c.68-7del variant is not a canonical +/-1,2 splice-site change and no RNA study showing an abnormal transcript was identified. Available evidence therefore does not support applying PVS1.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	PS1 can be used for intronic or exonic variants with the same predicted splicing effect as a previously classified pathogenic or likely pathogenic variant, but no verified comparator with the same predicted splice outcome was identified here.	cspec
PS2	N/A	This VCEP does not use PS2 for BRCA2 variant interpretation.	cspec
PS3	Not assessed	No published functional study showing a damaging effect for BRCA2 c.68-7del was identified, and this variant was not found in the curated ENIGMA functional assay table reviewed for PS3/BS3 use.	vcep_specifications_table9_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18
PS4	Not assessed	No case-control or quantitative prevalence data showing a significant enrichment of this variant in affected individuals versus controls were identified, so PS4 is not established.	cspec vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
PM1	N/A	PM1 is not used as an independent criterion in this BRCA2 specification and is instead considered within the bioinformatic framework for other codes.	cspec
PM2	Not met	This variant is present in population databases and therefore is not absent from controls. In addition, the BRCA2 specification states that PM2_Supporting should not be applied for insertion, deletion, or delins variants.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified that this variant was observed in trans with another BRCA2 pathogenic or likely pathogenic variant in an individual with BRCA2-related Fanconi anemia, so PM3 cannot be applied.	cspec
PM4	N/A	PM4 is not used by this BRCA2 VCEP.	cspec
PM5	N/A	In this BRCA2 specification, PM5 is repurposed for protein-truncating variant logic rather than classic same-residue missense comparison. This intronic c.68-7del variant is not a protein-truncating variant, so PM5 is not applicable.	cspec pm5_candidates vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	This VCEP does not use PM6 for BRCA2 variant interpretation.	cspec
PP1	Not assessed	No quantitative cosegregation data were identified for this variant, so PP1 cannot be applied.	cspec
PP2	N/A	PP2 is not used by this BRCA2 VCEP.	cspec
PP3	Not met	SpliceAI predicts no significant splice impact for this intronic variant, with a maximum delta score of 0.04, which is below the BRCA2 PP3 threshold of 0.2. Available computational evidence therefore does not support PP3.	spliceai cspec
PP4	Not assessed	No exact variant-level clinical-history likelihood ratio was identified for BRCA2 c.68-7del in the reviewed ENIGMA clinical-history materials, so PP4 was not established.	cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
PP5	N/A	PP5 is not used by this VCEP.	cspec
BA1	Met	This variant is too common for a pathogenic BRCA2 variant under the ENIGMA frequency framework. In gnomAD v2.1, the grpmax filter allele frequency is 0.00155833, which is above the BA1 threshold of 0.001 in a non-founder population.	gnomad_v2 gnomad_v4 cspec
BS1	Met	This variant exceeds the BRCA2 BS1 frequency threshold. In gnomAD v2.1, the grpmax filter allele frequency is 0.00155833, which is above the BS1 strong threshold of 0.0001.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No point-based evidence from individuals lacking features of BRCA2-related Fanconi anemia was identified to support BS2 under the BRCA2 specification.	cspec
BS3	Not assessed	No calibrated functional study showing no damaging effect for BRCA2 c.68-7del was identified, and this variant was not found in the curated ENIGMA functional assay table for BS3 use.	vcep_specifications_table9_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18
BS4	Not assessed	No quantitative nonsegregation data were identified for this variant, so BS4 cannot be applied.	cspec
BP1	N/A	BP1 in this BRCA2 specification applies to silent, missense, or in-frame coding variants outside clinically important domains with no predicted splice impact. This intronic deletion does not fit that variant class.	cspec
BP2	N/A	BP2 is not used by this BRCA2 VCEP.	cspec
BP3	N/A	BP3 is not used by this BRCA2 VCEP.	cspec
BP4	Met	This intronic variant is outside the native donor and acceptor +/-1,2 splice sites, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.04, which is below the BRCA2 BP4 threshold of 0.1. This supports BP4.	spliceai cspec
BP5	Not assessed	No exact variant-level clinical-history likelihood ratio was identified for BRCA2 c.68-7del in the reviewed ENIGMA clinical-history materials, so BP5 was not established.	cspec vcep_pmid_31853058_brca2_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	N/A	For intronic variants, BP7 in this BRCA2 specification is limited to positions at or beyond +7 or -21 when BP4 is met, or to RNA studies showing no damaging transcript effect. This c.68-7del variant is at position -7 and no benign RNA study was identified.	cspec spliceai

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