Variant classification summary

NM_000059.4:c.1813del

BRCA2 · NP_000050.3:p.(Ile605TyrfsTer9) · NM_000059.4

GRCh37: chr13:32907420 GA>G · GRCh38: chr13:32333283 GA>G

Gene: BRCA2 Transcript: NM_000059.4

Final call

Likely Pathogenic

PVS1 very strong PP5 supporting BS1 supporting

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Ile605TyrfsTer9)

gnomAD AF

9.367681498829039e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Very Strong): frameshift deletion in exon 11 creates a premature stop predicted to trigger nonsense-mediated decay.

2

PP5 (Supporting): the ENIGMA expert panel classifies this variant as Pathogenic in ClinVar.

3

BS1 (Supporting, benign-direction): population frequency (gnomAD grpmax FAF 2.96x10^-5) falls within the benign supporting range.

4

Overall: combining these criteria under the ENIGMA point-based system yields a net score of 8, supporting Likely Pathogenic.

Final determination: ENIGMA BRCA1/BRCA2 CSpec v1.2 Table 3 point system (8+1-1=8, Likely Pathogenic range 6-9), consistent with naive rule 1 Very Strong + 1 Supporting = Likely Pathogenic.

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	Met	Met (Very Strong): frameshift creates a premature stop at codon 613 in exon 11, predicted to trigger nonsense-mediated decay.	cspec pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	Not assessed: insufficient evidence was available to evaluate this criterion.
PS2	N/A	Not applicable: BRCA2 has no calibrated de novo-occurrence data, so this criterion cannot be used for this gene.	cspec
PS3	N/A	Not applicable: functional-assay evidence for BRCA2 applies only to missense or synonymous variants, not this frameshift.
PS4	Not assessed	Not assessed: no case-control enrichment data (odds ratio or p-value) was available for this variant.
PM1	Not assessed	Not assessed: insufficient evidence was available to evaluate this criterion.
PM2	Not met	Not met: variant is present in gnomAD controls (AF up to 3.4x10^-5), so it is not absent as required.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no proband-level Fanconi anemia phenotype or co-occurring variant data was available.
PM4	N/A	Not applicable: this is a frameshift deletion, not an in-frame length change or stop-loss variant.	pvs1_variant_assessment
PM5	Not assessed	Not assessed: insufficient evidence was available to evaluate this criterion.
PM6	N/A	Not applicable: BRCA2 has no calibrated de novo-occurrence data, and no unconfirmed-parentage information was available.	cspec
PP1	Not assessed	Not assessed: no family segregation data or likelihood ratio was available for this variant.
PP2	Not assessed	Not assessed: insufficient evidence was available to evaluate this criterion.
PP3	N/A	Not applicable: this criterion covers missense, splicing, or in-frame variants, and does not apply to this frameshift deletion.	cspec spliceai pvs1_variant_assessment
PP4	Not assessed	Not assessed: no variant-specific clinical-history likelihood ratio was available.
PP5	Met	Met (Supporting): the ENIGMA expert panel classifies this variant as Pathogenic in ClinVar.	clinvar
BA1	Not met	Not met: highest population frequency (gnomAD grpmax FAF ~3x10^-5) is far below the 0.1% stand-alone benign threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Met	Met (Supporting): gnomAD v2.1 grpmax frequency of 2.96x10^-5 falls within the benign supporting frequency range.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no proband-level clinical data was available to score absence of Fanconi anemia features.	gnomad_v2 gnomad_v4
BS3	N/A	Not applicable: benign functional-assay evidence for BRCA2 applies only to missense or synonymous variants, not this frameshift.
BS4	Not assessed	Not assessed: no quantitative non-segregation data was available for this variant.
BP1	Not assessed	Not assessed: insufficient evidence was available to evaluate this criterion.
BP2	N/A	Not applicable: this criterion is not used for BRCA2 under the governing expert panel specification.	cspec
BP3	N/A	Not applicable: this criterion is not used for BRCA2, and also does not fit a frameshift deletion.	cspec pvs1_variant_assessment
BP4	N/A	Not applicable: this criterion covers missense, splicing, or in-frame variants, and does not apply to this frameshift deletion.	cspec spliceai pvs1_variant_assessment
BP5	Not assessed	Not assessed: no variant-specific clinical-history likelihood ratio was available.
BP6	N/A	Not applicable: no benign or likely-benign expert-panel classification exists for this variant in ClinVar.	clinvar
BP7	N/A	Not applicable: this criterion covers intronic or synonymous variants, and does not apply to this frameshift deletion.	cspec pvs1_variant_assessment

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