Variant classification summary

NM_000059.4:c.4284dup

BRCA2 · NP_000050.3:p.(Gln1429SerfsTer9) · NM_000059.4

GRCh37: chr13:32912770 A>AT · GRCh38: chr13:32338633 A>AT

Gene: BRCA2 Transcript: NM_000059.4

Final call

Pathogenic

PVS1 very strong PM5 strong PP4 supporting PP5 supporting

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Gln1429SerfsTer9)

gnomAD AF

1.063329396929605e-05 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000059.4:c.4284dup is a frameshift duplication in BRCA2 exon 11, predicted to generate a premature termination codon at p.(Gln1429SerfsTer9) with expected NMD.

2

PVS1 (very strong) is applied per ENIGMA Specifications Table 4, which assigns PVS1 to BRCA2 exon 11 PTC variants. BRCA2 loss of function is an established mechanism for hereditary breast and ovarian cancer.

3

PM5_Strong (PTC) is applied per ENIGMA Table 4, reflecting that exon 11 harbors multiple proven pathogenic PTC variants supporting additional weight beyond PVS1.

4

PP4_Supporting is applied based on clinical history likelihood ratio of 2.23 from 21 probands in the Li et al. 2020 cohort, exceeding the ENIGMA PP4 supporting threshold of LR ≥ 2.08.

5

PP5_Supporting is applied per standing adjudication rule: ClinVar classifies this variant as Pathogenic with ENIGMA expert panel review (3-star), warranting PP5 at supporting strength.

6

Under ENIGMA Table 3 combining rules, 1×PVS1 (very strong) + 1×PM5_Strong (strong) satisfies the pathogenic classification threshold (1×Very Strong + ≥1×Strong). Additionally, 1×Very Strong + ≥2×Supporting (PP4 + PP5) independently meets the pathogenic threshold.

7

Final classification: PATHOGENIC, consistent with the ENIGMA expert panel classification in ClinVar (Variation ID 37892).

Final determination: ENIGMA Table 3: 1×Very Strong (PVS1) + 1×Strong (PM5) satisfies the Pathogenic threshold; independently, 1×Very Strong (PVS1) + 2×Supporting (PP4 + PP5) also meets 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	NM_000059.4:c.4284dup is a frameshift duplication in BRCA2 exon 11 (c.1910-6841) predicted to cause a premature termination codon at p.(Gln1429SerfsTer9). Per ENIGMA Specifications Table 4, BRCA2 exon 11 PTC variants are assigned PVS1 (very strong). BRCA2 loss of function is an established disease mechanism for hereditary breast and ovarian cancer. NMD is expected given the truncation occurs well upstream of the final exon.	vcep_specifications_table4_v1_2_2024_11_18 cspec pvs1_gene_context pvs1_variant_assessment
PS1	N/A	ENIGMA PS1 applies only to missense substitutions or variants with predicted splicing impact comparable to a known pathogenic variant. NM_000059.4:c.4284dup is a frameshift duplication and is not eligible for PS1 per the ENIGMA specification.	cspec
PS2	N/A	ENIGMA specification marks PS2 as Not Applicable for BRCA2.	cspec
PS3	Not met	No variant-specific functional studies were identified for NM_000059.4:c.4284dup. ENIGMA Specifications Table 9 (curated functional assay results) covers missense and synonymous variants only and does not list c.4284dup. Full-text review of available publications did not identify functional characterization of this variant. General domain-level or truncation-mechanism inference does not satisfy PS3 requirements.	vcep_specifications_table9_v1_2_2024_11_18
PS4	Not assessed	ENIGMA PS4 requires a formal case-control study with odds ratio ≥4 and lower confidence interval excluding 2.0. No dedicated case-control study for c.4284dup was identified in the evidence brief or literature review. The variant has been observed in 21 probands in the Li et al. 2020 clinical history cohort, but this does not constitute a case-control comparison.	cspec
PS5	N/A	Not in the assess list; ENIGMA specification does not define PS5 for BRCA2.
PM1	N/A	ENIGMA specification marks PM1 as Not Applicable for BRCA2.	cspec
PM2	Not met	ENIGMA PM2_Supporting requires the variant to be absent from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer). This variant is present in gnomAD v2.1 with 1 allele (AF=4.09e-6, NFE_SEU subpopulation) and in gnomAD v4.1 with 17 alleles (grpmax FAF=6.94e-6). The variant is not absent and therefore does not meet the ENIGMA PM2 criterion.	gnomad_v2 gnomad_v4 cspec
PM4	N/A	ENIGMA specification marks PM4 as Not Applicable for BRCA2.	cspec
PM5	Met	Per ENIGMA Specifications Table 4, BRCA2 exon 11 PTC variants are assigned PM5_Strong (PTC). Exon 11 is not in the PM5_N/A exclusion list (E12, E27, E6). This criterion provides additional weight for PTC variants already annotated as PVS1, reflecting the established pathogenicity of other PTC variants in this exon.	vcep_specifications_table4_v1_2_2024_11_18 cspec
PM6	N/A	ENIGMA specification marks PM6 as Not Applicable for BRCA2.	cspec
PP1	Not assessed	ENIGMA PP1 requires quantitative cosegregation analysis with likelihood ratio ≥2.08. No cosegregation data for NM_000059.4:c.4284dup was identified in the evidence brief or literature review.	cspec
PP2	N/A	ENIGMA specification marks PP2 as Not Applicable for BRCA2.	cspec
PP3	Not met	SpliceAI predicts no splice impact (max delta score = 0.00). The variant is a frameshift duplication, which falls outside ENIGMA PP3 applicability (PP3 is defined for missense/in-frame variants in functional domains with BayesDel ≥0.30, or for variants with SpliceAI ≥0.20). Neither threshold is met.	spliceai cspec
PP4	Met	Per ENIGMA PP4, the clinical history likelihood ratio from Li et al. 2020 (PMID:31853058) for BRCA2 c.4284dup is LR=2.23 based on 21 probands, exceeding the PP4_Supporting threshold of LR≥2.08. This indicates that the personal and family cancer history of carriers is more consistent with a pathogenic variant than with a benign finding.	PMID:31853058 vcep_pmid_31853058_brca2_clinical_history_lr cspec
PP5	Met	Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Pathogenic.	clinvar cspec
BA1	Not met	ENIGMA BA1 requires filter allele frequency (FAF) > 0.001 (0.1%) in gnomAD non-cancer populations. The grpmax FAF for this variant is 6.94e-6 (0.00069%) in gnomAD v4.1, which is approximately 144-fold below the BA1 threshold.	gnomad_v4 cspec
BS1	Not met	ENIGMA BS1_Supporting requires FAF > 0.00002 (0.002%) and BS1_Strong requires FAF > 0.0001 (0.01%). The grpmax FAF is 6.94e-6, which falls below even the BS1_Supporting threshold.	gnomad_v4 cspec
BS2	Not assessed	ENIGMA BS2 requires evaluation of Fanconi Anemia phenotype and point-based scoring per Specifications Table 8. No Fanconi Anemia phenotype data was available for this variant.	cspec
BS3	Not assessed	ENIGMA Table 9 (curated functional assay results for BS3) covers missense and synonymous variants only. No BS3-relevant functional data for this frameshift variant was identified.	vcep_specifications_table9_v1_2_2024_11_18
BS4	Not assessed	ENIGMA BS4 requires quantitative lack-of-segregation analysis with likelihood ratio ≤0.48. No segregation data for c.4284dup was identified.	cspec
BP1	N/A	ENIGMA BP1 applies to silent substitutions, missense variants, or in-frame insertions/deletions outside clinically important functional domains with no splicing predicted. NM_000059.4:c.4284dup is a frameshift duplication and is not eligible for BP1.	cspec
BP2	N/A	ENIGMA specification marks BP2 as Not Applicable for BRCA2.	cspec
BP3	N/A	ENIGMA specification marks BP3 as Not Applicable for BRCA2.	cspec
BP4	N/A	ENIGMA BP4 applies to missense or in-frame insertion/deletion/delins variants inside a clinically important functional domain with no predicted impact. NM_000059.4:c.4284dup is a frameshift duplication and is not eligible for BP4.	cspec
BP5	Not met	The clinical history LR from Li et al. 2020 (PMID:31853058) is 2.23, which favors pathogenicity. ENIGMA BP5 requires LR ≤0.48 for supporting benign evidence. An LR >1.0 is incompatible with BP5 application.	PMID:31853058 vcep_pmid_31853058_brca2_clinical_history_lr cspec
BP6	N/A	ClinVar classification for this variant is Pathogenic (expert panel). BP6 requires a benign or likely benign consensus. The standing PP5/BP6 rule applies PP5_Supporting for 3-star EP pathogenic classifications; BP6 is not applicable to variants classified as pathogenic by expert panel.	clinvar cspec
BP7	Not assessed	ENIGMA BP7 requires well-established in vitro/in vivo functional studies showing no damaging effect on mRNA transcript profile (mRNA assay only). No mRNA assay data for c.4284dup was identified.	cspec

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