Final classification

Likely Pathogenic

PVS1PP5

BRCA2

c.6859A>T

p.Arg2287Ter

This variant

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.

Transcript

NM_000059.3

HGVS · transcript:coding

NM_000059.3:c.6859A>T

GRCh38

chr13:32344575 A>T

GRCh37

chr13:32918712 A>T

ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3 final-classification framework (CSPEC/VCEP override) applied to the authoritative adjudicated criteria.

Classification rationale

PVS1PP5 Likely Pathogenic

BRCA2 c.6859A>T

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.¹ 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.² 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 12.³ SpliceAI predicts no significant splice impact, with a maximum delta score of 0.10, which does not support PP3 for splice disruption.⁴

PVS1 + PP5 → Likely Pathogenic

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 cspec ↗vcep_specifications_table4_v1_2_2024_11_18pvs1_gene_contextpvs1_variant_assessment

4 spliceai ↗cspec ↗

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_000059.3 · variants mapped to exon structure

BRCA2 NM_000059.3

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 13 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PVS1 very strong review Pathogenic

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.

Protein consequence is p.(Arg2287Ter).Variant maps to exon 12.BRCA2 exon 12 PTC row is annotated PVS1 in the ENIGMA table.

cspec ↗

PP5 supporting Pathogenic

Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic.

BRCA2 ENIGMA specification marks PP5 as not applicable.ClinVar expert panel classification

cspec ↗clinvar ↗

Assessed · not applied · 4 not met · 9 not assessed

Pathogenic

PS1 No previously classified variant with the same proven protein change or the same established splice effect was identified for this variant.

PS3 No variant-specific calibrated functional assay result supporting a damaging effect was identified in the reviewed ENIGMA functional table for this variant.

PS4 No case-control enrichment result or quantitative affected-versus-control evidence meeting ENIGMA PS4 requirements was identified for this variant.

PM2 Available population data do not show complete absence from controls.

PM3 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.

PP1 No segregation data were identified showing that this variant tracks with disease in affected relatives.

PP4 No variant-specific clinical-history likelihood ratio meeting ENIGMA PP4 thresholds was identified.

Benign

BA1 Population frequency is far below the ENIGMA BA1 threshold.

BS1 Population frequency is far below the ENIGMA BS1 thresholds.

BS2 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.

BS3 No variant-specific calibrated functional assay result showing no damaging effect was identified in the reviewed ENIGMA functional table for this variant.

BS4 No nonsegregation data were identified showing that this variant fails to track with disease in affected relatives.

BP5 No variant-specific clinical-history likelihood ratio meeting ENIGMA BP5 thresholds was identified.

N/A · 13 PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP3 · BP1 · BP2 · BP3 · BP4 · BP6 · BP7

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 6.42629e-07; MAF= 0.00006%, 1/1556108 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.84903e-07; MAF= 0.00009%, 1/1130068 alleles, homozygotes = 0).

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

6.4e-05% · 1 / 1,556,108
0 hom

European (non-Finnish)

1 / 1,130,068

8.8e-05%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratory) and as Pathogenic (1 clinical laboratory) and as likely pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10). BayesDel score = 0.566539.

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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