Classification rationale

PVS1PP5 BS1 Likely Pathogenic

BRCA2 c.1813del frameshift · exon 10

PVS1 (Very Strong): frameshift deletion in exon 11 creates a premature stop predicted to trigger nonsense-mediated decay. PP5 (Supporting): the ENIGMA expert panel classifies this variant as Pathogenic in ClinVar. BS1 (Supporting, benign-direction): population frequency (gnomAD grpmax FAF 2.96x10^-5) falls within the benign supporting range. Overall: combining these criteria under the ENIGMA point-based system yields a net score of 8, supporting Likely Pathogenic.

PVS1 + PP5 + BS1 → Likely Pathogenic

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

BRCA2 NM_000059.4

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 14 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): frameshift creates a premature stop at codon 613 in exon 11, predicted to trigger nonsense-mediated decay.

cspec (ENIGMA BRCA2 Specification v1.2): PVS1 default strength Very Strong for null variants including frameshift in a gene with established LOF mechanism.pvs1_gene_context.json: germline LOF mechanism confirmed for BRCA2 based on CSPEC/VCEP PVS1 guidance presence (pvs1_gene_gate = eligible).pvs1_variant_assessment.json: variant classified as frameshift consequence class, generic PVS1 framework (PMC6185798) applies, suggested default strength PVS1 (Very Strong), pending confirmation of transcript relevance/NMD/exon importance.

cspec ↗pvs1_generic_framework ↗

PP5 supporting Pathogenic

Met (Supporting): the ENIGMA expert panel classifies this variant as Pathogenic in ClinVar.

ClinVar VCV000037763 shows an ENIGMA expert-panel (SCV000282362) submission classifying NM_000059.4:c.1813del as Pathogenic, review status 'reviewed by expert panel' (3-star), date last evaluated 2016-04-22, in addition to 26 other clinical-laboratory Pathogenic submissions.Per case policy: PP5 applies at supporting strength for any exact-variant ClinVar 3-star expert-panel Pathogenic/Likely pathogenic classification, overriding the ENIGMA VCEP's internal 'Not Applicable' flag for PP5 (which exists only to prevent double-counting within ENIGMA's own scoring, not to negate ClinVar EP evidence generally).ClinVar expert panel classification

clinvar ↗

BS1 supporting Benign

Met (Supporting): gnomAD v2.1 grpmax frequency of 2.96x10^-5 falls within the benign supporting frequency range.

gnomAD v2.1 grpmax FAF = 2.955e-05 (South Asian subpopulation, 3/26880 alleles), within the BS1_Supporting band (0.00002, 0.0001].gnomAD v4.1 grpmax FAF = 1.397e-05 (Admixed American subpopulation, 3/56988 alleles), below the 0.00002 lower bound on its own.

gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 2 not met · 12 not assessed

Pathogenic

PS1 Not assessed: insufficient evidence was available to evaluate this criterion.

PS4 Not assessed: no case-control enrichment data (odds ratio or p-value) was available for this variant.

PM1 Not assessed: insufficient evidence was available to evaluate this criterion.

PM2 Not met: variant is present in gnomAD controls (AF up to 3.4x10^-5), so it is not absent as required.

PM3 Not assessed: no proband-level Fanconi anemia phenotype or co-occurring variant data was available.

PM5 Not assessed: insufficient evidence was available to evaluate this criterion.

PP1 Not assessed: no family segregation data or likelihood ratio was available for this variant.

PP2 Not assessed: insufficient evidence was available to evaluate this criterion.

PP4 Not assessed: no variant-specific clinical-history likelihood ratio was available.

Benign

BA1 Not met: highest population frequency (gnomAD grpmax FAF ~3x10^-5) is far below the 0.1% stand-alone benign threshold.

BS2 Not assessed: no proband-level clinical data was available to score absence of Fanconi anemia features.

BS4 Not assessed: no quantitative non-segregation data was available for this variant.

BP1 Not assessed: insufficient evidence was available to evaluate this criterion.

BP5 Not assessed: no variant-specific clinical-history likelihood ratio was available.

N/A · 11 PS2 · PS3 · PM4 · PM6 · PP3 · BS3 · 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= 9.36768e-06; MAF= 0.00094%, 15/1601250 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 5.26427e-05; MAF= 0.00526%, 3/56988 alleles, homozygotes = 0); grpmax FAF= 1.397e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 3.4467e-05; MAF= 0.00345%, 8/232106 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000111607; MAF= 0.01116%, 3/26880 alleles, homozygotes = 0); grpmax FAF= 2.955e-05.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00094% · 15 / 1,601,250
0 hom · FAF 0.0014%

Admixed American 3 / 56,988	0.0053%
East Asian 2 / 44,798	0.0045%
South Asian 3 / 88,210	0.0034%
European (non-Finnish) 7 / 1,175,924	0.0006%

+ 6 not observed (Remaining individuals, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0034% · 8 / 232,106
0 hom · FAF 0.003%

South Asian 3 / 26,880	0.011%
Admixed American 3 / 30,762	0.0098%
European (non-Finnish) 2 / 106,112	0.0019%

+ 5 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals)

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 (26 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 = 37763)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

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; COSV66449038, n = 15 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

11802209 ↗ Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population. CLINVAR

18824701 ↗ Clinically applicable models to characterize BRCA1 and BRCA2 variants of uncertain significance. CLINVAR

19016756 ↗ Cross-sectional analysis of germline BRCA1 and BRCA2 mutations in Japanese patients suspected to have hereditary breast/ovarian cancer. CLINVAR