Variant classification summary

NM_000059.3:c.6859A>T

BRCA2 · NP_000050.2:p.(Arg2287Ter) · NM_000059.3

GRCh37: chr13:32918712 A>T · GRCh38: chr13:32344575 A>T

Gene: BRCA2 Transcript: NM_000059.3

Final call

Likely Pathogenic

Variant details

Gene

BRCA2

Transcript

NM_000059.3

Protein

NP_000050.2:p.(Arg2287Ter)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA2 c.6859A>T (p.Arg2287Ter; p.R2287*) variant has not been observed in COSMIC and has been reported in ClinVar as Pathogenic with expert panel review.

2

This variant is absent from gnomAD v2.1 and is present once in gnomAD v4.1 (1/1,556,108 alleles; AF 6.43e-07; no homozygotes), consistent with extreme rarity.

3

Under the ENIGMA BRCA2 specification, this exon 12 premature termination variant is a null variant in a gene where loss of function is an established disease mechanism, and the exon-level table assigns PVS1 to protein-truncating variants in exon 12.

4

SpliceAI predicts no significant splice impact, with a maximum delta score of 0.10, which does not support PP3 for splice disruption.

Final determination: Under the ENIGMA BRCA1/BRCA2 Table 3 combining rules, 1 Very Strong pathogenic criterion together with 1 Supporting pathogenic criterion meets the threshold for 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	This variant is a nonsense change, NM_000059.3:c.6859A>T (p.Arg2287Ter), in BRCA2, a gene in which loss of function is an established disease mechanism. The ENIGMA BRCA2 exon-level table assigns PVS1 to protein-truncating variants in exon 12; this variant lies in exon 12.	cspec vcep_specifications_table4_v1_2_2024_11_18 pvs1_gene_context pvs1_variant_assessment
PS1	Not met	No previously classified variant with the same proven protein change or the same established splice effect was identified for this variant. This change is a nonsense variant, and available splice prediction does not show a pathogenic-equivalent splice effect.	cspec spliceai
PS2	N/A	This criterion is not used in the BRCA2 ENIGMA specification.	cspec
PS3	Not assessed	No variant-specific calibrated functional assay result supporting a damaging effect was identified in the reviewed ENIGMA functional table for this variant.	vcep_specifications_table9_v1_2_2024_11_18 oncokb
PS4	Not assessed	No case-control enrichment result or quantitative affected-versus-control evidence meeting ENIGMA PS4 requirements was identified for this variant.	cspec vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
PM1	N/A	This criterion is not applied for BRCA2 in the ENIGMA specification.	cspec
PM2	Not met	Available population data do not show complete absence from controls. The variant is absent from gnomAD v2.1 but is present once in gnomAD v4.1 (1/1,556,108 alleles; AF 6.43e-07; no homozygotes), so the ENIGMA absence requirement is not fully satisfied.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified that this variant was observed with another BRCA2 variant in a patient with a phenotype consistent with BRCA2-related Fanconi anemia.	cspec
PM4	N/A	This criterion is not used in the BRCA2 ENIGMA specification.	cspec
PM5	N/A	This is a protein-truncating variant in exon 12, and the ENIGMA BRCA2 exon-level table marks exon 12 as PM5_N/A for PTC-based PM5 application.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	This criterion is not used in the BRCA2 ENIGMA specification.	cspec
PP1	Not assessed	No segregation data were identified showing that this variant tracks with disease in affected relatives.	cspec
PP2	N/A	This criterion is not used in the BRCA2 ENIGMA specification.	cspec
PP3	N/A	This variant is a nonsense change rather than a missense, in-frame, silent, or noncanonical intronic variant targeted by the BRCA2 ENIGMA PP3 bioinformatic rule. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.10, which is below the PP3 splice threshold of 0.20.	cspec spliceai bayesdel
PP4	Not assessed	No variant-specific clinical-history likelihood ratio meeting ENIGMA PP4 thresholds was identified. Review of the BRCA2 clinical-history likelihood-ratio workbook did not find an exact entry for this variant.	cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
PP5	Met	Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic.	cspec clinvar
BA1	Not met	Population frequency is far below the ENIGMA BA1 threshold. In gnomAD v4.1 the variant is present at 1/1,556,108 alleles (AF 6.43e-07; 0.000064%), which is well below the BA1 threshold of greater than 0.1%.	cspec gnomad_v4
BS1	Not met	Population frequency is far below the ENIGMA BS1 thresholds. In gnomAD v4.1 the highest observed population frequency is 8.85e-07 (0.000089%) in European non-Finnish individuals, which is below the BS1 supporting threshold of greater than 0.00002 and far below the strong threshold of greater than 0.0001.	cspec gnomad_v4
BS2	Not assessed	No data were identified showing this variant in individuals without features of BRCA2-related Fanconi anemia in the point-based framework required for BRCA2 BS2.	cspec
BS3	Not assessed	No variant-specific calibrated functional assay result showing no damaging effect was identified in the reviewed ENIGMA functional table for this variant.	vcep_specifications_table9_v1_2_2024_11_18
BS4	Not assessed	No nonsegregation data were identified showing that this variant fails to track with disease in affected relatives.	cspec
BP1	N/A	This criterion is intended for silent, missense, or in-frame variants outside clinically important domains without splice impact, and does not apply to this nonsense variant.	cspec spliceai
BP2	N/A	This criterion is not used in the BRCA2 ENIGMA specification.	cspec
BP3	N/A	This criterion is not used in the BRCA2 ENIGMA specification.	cspec
BP4	N/A	This criterion is targeted to missense, in-frame, silent, or intronic variants without predicted splice impact in specific contexts, and does not apply to this nonsense variant. SpliceAI predicts no significant splice effect, with a maximum delta score of 0.10.	cspec spliceai bayesdel
BP5	Not assessed	No variant-specific clinical-history likelihood ratio meeting ENIGMA BP5 thresholds was identified. Review of the BRCA2 clinical-history likelihood-ratio workbook did not find an exact entry for this variant.	cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
BP6	N/A	This criterion is not used in the BRCA2 ENIGMA specification.	cspec
BP7	N/A	This criterion is designed for silent or certain intronic variants, and does not apply to this nonsense variant. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.10, but BP7 is not the relevant framework for a protein-truncating change.	cspec spliceai

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