Variant classification summary

NM_000059.4:c.8537_8538del

BRCA2 · NP_000050.3:p.(Glu2846GlyfsTer22) · NM_000059.4

GRCh37: chr13:32945137 AAG>A · GRCh38: chr13:32371000 AAG>A

Gene: BRCA2 Transcript: NM_000059.4

Final call

Pathogenic

PVS1 very strong PM5 strong PP5 supporting

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Glu2846GlyfsTer22)

gnomAD AF

6.195065258817436e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Very Strong): two-base deletion creates frameshift p.(Glu2846GlyfsTer22) predicted to trigger nonsense-mediated decay.

2

PM5 (Strong): premature-termination frameshift in exon 20, assigned PM5_Strong by the ENIGMA BRCA2 rule.

3

PP5 (Supporting): the ENIGMA expert panel classified this variant as Pathogenic.

4

Overall classification: Pathogenic, per the ENIGMA BRCA2 combination rule requiring PVS1 Very Strong plus one Strong criterion.

Final determination: Under ENIGMA BRCA2 v1.2 Table 3, one Very Strong pathogenic criterion plus at least one Strong pathogenic criterion classifies the variant as 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): the two-base deletion creates frameshift p.(Glu2846GlyfsTer22), predicted to trigger nonsense-mediated decay.	cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PS1	N/A	Not applicable: PS1 requires the same missense substitution or matched splice event; this is a frameshift.	cspec vcep_specifications_v1_2_2024_11_18
PS2	N/A	Not applicable: the ENIGMA BRCA2 framework designates PS2 (de novo evidence) as not used.	cspec
PS3	Not assessed	Not assessed: no variant-specific validated protein-function assay was available.	cspec vcep_specifications_table9_v1_2_2024_11_18
PS4	Not assessed	Not assessed: no case-control study of this exact variant met the required p<=0.05 with OR>=4.	cspec
PM1	N/A	Not applicable: the ENIGMA BRCA2 specification does not use PM1.	cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM2	Not met	Not met: observed in gnomAD v2.1 (3/251,142 alleles) and v4.1, so not absent from controls as required.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no co-occurring pathogenic BRCA2 variant or phase information was available.	cspec
PM4	N/A	Not applicable: designated not used by the ENIGMA BRCA2 specification; frameshifts are assessed under PVS1.	cspec vcep_specifications_v1_2_2024_11_18
PM5	Met	Met (Strong): premature-termination frameshift in exon 20, assigned PM5_Strong by ENIGMA Table 4.	cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	Not applicable: the ENIGMA BRCA2 framework designates PM6 as not used.	cspec
PP1	Not assessed	Not assessed: no quantitative co-segregation analysis was available.	cspec
PP2	N/A	Not applicable: ENIGMA designates PP2 as not used for BRCA2 due to high benign missense burden.	cspec vcep_specifications_v1_2_2024_11_18
PP3	N/A	Not applicable: bioinformatic rule covers only missense/in-frame variants; SpliceAI max delta is 0.045.	cspec spliceai
PP4	Not assessed	Not assessed: no multifactorial clinical-data likelihood ratio was available.	cspec vcep_pmid_31853058_brca2_clinical_history_lr
PP5	Met	Met (Supporting): the ENIGMA expert panel classified this variant as Pathogenic.	clinvar
BA1	Not met	Not met: gnomAD v2.1 grpmax FAF 0.000703% is far below the >0.1% BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: highest group FAF 7.03e-06 (gnomAD v2.1) is below the BS1_Supporting threshold of 0.00002.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: Fanconi anemia phenotype and chromosome-breakage data were not available.	cspec
BS3	Not assessed	Not assessed: no benign calibrated functional assay result was available for this variant.	cspec vcep_specifications_table9_v1_2_2024_11_18
BS4	Not assessed	Not assessed: no quantitative non-segregation analysis was available.	cspec
BP1	N/A	Not applicable: BP1_Strong covers only silent, missense, or in-frame changes; this is a truncating frameshift.	cspec vcep_specifications_v1_2_2024_11_18
BP2	N/A	Not applicable: the ENIGMA BRCA2 specification designates BP2 as not used.	cspec
BP3	N/A	Not applicable: the ENIGMA BRCA2 specification designates BP3 as not used.	cspec vcep_specifications_v1_2_2024_11_18
BP4	N/A	Not applicable: this exonic frameshift is outside all BP4 variant classes despite SpliceAI max delta 0.045.	cspec spliceai
BP5	Not assessed	Not assessed: no multifactorial likelihood ratio against pathogenicity was available.	cspec vcep_pmid_31853058_brca2_clinical_history_lr
BP6	Not met	Not met: the ClinVar ENIGMA expert-panel assertion is Pathogenic, not Benign or Likely benign.	clinvar
BP7	N/A	Not applicable: BP7 covers intronic, silent, and missense/in-frame variants only; this is a frameshift.	cspec spliceai

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