Classification rationale

PVS1PM5PP5 Pathogenic

BRCA2 c.8537_8538del frameshift · exon 20

PVS1 (Very Strong): two-base deletion creates frameshift p.(Glu2846GlyfsTer22) predicted to trigger nonsense-mediated decay. PM5 (Strong): premature-termination frameshift in exon 20, assigned PM5_Strong by the ENIGMA BRCA2 rule. PP5 (Supporting): the ENIGMA expert panel classified this variant as Pathogenic. Overall classification: Pathogenic, per the ENIGMA BRCA2 combination rule requiring PVS1 Very Strong plus one Strong criterion.

PVS1 + PM5 + PP5 → Pathogenic

Gene diagram · NM_000059.4 · variants mapped to exon structure

BRCA2 NM_000059.4

Fetching transcript structure from UCSC…

Applied criteria · 3 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 · 3

Strength Supporting Moderate Strong Very strong

✓

PVS1 very strong Pathogenic

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

The normalized consequence on the ENIGMA preferred transcript NM_000059.4 is NP_000050.3:p.(Glu2846GlyfsTer22), a frameshift with a premature termination codon 22 codons downstream.ENIGMA BRCA1/BRCA2 v1.2 specifies PVS1 for null variants in BRCA2, with strength determined by its PVS1 flowchart and Table 4 exon-level decision table.The ENIGMA BRCA2 Table 4 summary identifies exon 20 as PVS1-applicable; only exons 6, 12, and 27 are designated PVS1_N/A in the supplied table summary.

cspec ↗

✓

PM5 strong Pathogenic

Met (Strong): premature-termination frameshift in exon 20, assigned PM5_Strong by ENIGMA Table 4.

ENIGMA BRCA2 VCEP v1.2 repurposes PM5 for an additional weight for a genomic protein-termination-codon variant when a different proven pathogenic PTC has been observed in the same exon; the weight is determined by exon.ENIGMA Specifications Table 4 places c.8537_8538del within exon 20 because exon 19 ends at c.8487 and exon 20 spans c.8488-c.8632; the exon 20 PTC row assigns PM5_Strong (PTC).The normalized protein consequence is NP_000050.3:p.(E2846Gfs*22), confirming a truncating PTC consequence; the variant is not at a canonical donor/acceptor +/-1,2 position.

cspec ↗

✓

PP5 supporting Pathogenic

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

ClinVar identifies the exact record as NM_000059.4(BRCA2):c.8537_8538del (p.Glu2846fs) and reports a Pathogenic expert-panel submission by ENIGMA.ClinVar expert panel classification

clinvar ↗

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

Pathogenic

PS3 Not assessed: no variant-specific validated protein-function assay was available.

PS4 Not assessed: no case-control study of this exact variant met the required p<=0.05 with OR>=4.

PM2 Not met: observed in gnomAD v2.1 (3/251,142 alleles) and v4.1, so not absent from controls as required.

PM3 Not assessed: no co-occurring pathogenic BRCA2 variant or phase information was available.

PP1 Not assessed: no quantitative co-segregation analysis was available.

PP4 Not assessed: no multifactorial clinical-data likelihood ratio was available.

Benign

BA1 Not met: gnomAD v2.1 grpmax FAF 0.000703% is far below the >0.1% BA1 threshold.

BS1 Not met: highest group FAF 7.03e-06 (gnomAD v2.1) is below the BS1_Supporting threshold of 0.00002.

BS2 Not assessed: Fanconi anemia phenotype and chromosome-breakage data were not available.

BS3 Not assessed: no benign calibrated functional assay result was available for this variant.

BS4 Not assessed: no quantitative non-segregation analysis was available.

BP5 Not assessed: no multifactorial likelihood ratio against pathogenicity was available.

BP6 Not met: the ClinVar ENIGMA expert-panel assertion is Pathogenic, not Benign or Likely benign.

N/A · 12 PS1 · PS2 · PM1 · PM4 · PM6 · PP2 · PP3 · BP1 · BP2 · BP3 · BP4 · BP7

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 6.19507e-06; MAF= 0.00062%, 10/1614188 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47443e-06; MAF= 0.00085%, 10/1180020 alleles, homozygotes = 0); grpmax FAF= 4.29e-06.

v2.1

This variant is present in gnomAD v2.1 (AF= 1.19454e-05; MAF= 0.00119%, 3/251142 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.64387e-05; MAF= 0.00264%, 3/113470 alleles, homozygotes = 0); grpmax FAF= 7.03e-06.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00062% · 10 / 1,614,188
0 hom · FAF 0.00043%

European (non-Finnish)

10 / 1,180,020

0.00085%

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

gnomAD v2.1

0.0012% · 3 / 251,142
0 hom · FAF 0.0007%

European (non-Finnish)

3 / 113,470

0.0026%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Pathogenic (25 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel). (ClinVarID = 9328)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).

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 previously been reported in somatic cancers (COSMIC; COSV105932270, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 8 PMIDs not cited in assessment

10570174 ↗ Truncated BRCA2 is cytoplasmic: implications for cancer-linked mutations. ONCOKB

11239455 ↗ BRCA2 is required for homology-directed repair of chromosomal breaks. ONCOKB

20878484 ↗ A new mutation of BRCA2 gene in an Italian healthy woman with familial breast cancer history. ONCOKB

22193408 ↗ BRCA1 and BRCA2: different roles in a common pathway of genome protection. ONCOKB

24312913 ↗ A comprehensive focus on global spectrum of BRCA1 and BRCA2 mutations in breast cancer. ONCOKB

11512557 ↗ Haplotype analysis of BRCA2 8765delAG mutation carriers in French Canadian and Yemenite Jewish hereditary breast cancer families. CLINVAR

17591843 ↗ Founder mutations in BRCA1 and BRCA2 genes. CLINVAR

17640379 ↗ Origin and distribution of the BRCA2-8765delAG mutation in breast cancer. CLINVAR