Classification rationale

BP1BP4 Likely Benign

BRCA2 c.9934A>G missense · exon 27

Likely Benign: BP1 strong because residue 3312 lies outside the defined BRCA2 functional domains and SpliceAI max delta is 0.014. Likely Benign: BP4 supporting because REVEL is 0.017, below the benign threshold for missense variants.

BP1 + BP4 → Likely Benign

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_000059.4 · variants mapped to exon structure

BRCA2 NM_000059.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 16 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

BP1 strong Benign

Met at Strong: residue 3312 is outside ENIGMA domains aa 10-40 and aa 2481-3186, with SpliceAI max delta 0.014 <=0.1.

ENIGMA V1.2 BP1 rule: BP1_Strong applies to missense or in-frame variants outside a potentially clinically important functional domain with no predicted splicing impact (SpliceAI <=0.1).The variant is missense p.Ile3312Val at residue 3312; the governing ENIGMA domains are aa 10-40 and aa 2481-3186, so residue 3312 is outside the domains.SpliceAI max delta is 0.014, below the ENIGMA BP1 threshold of 0.1.

cspec ↗spliceai ↗

BP4 supporting Benign

Met at supporting strength: REVEL 0.017 is below the BP4 supporting threshold of 0.29 for missense variants.

The case normalization identifies NM_000059.4:c.9934A>G as the missense variant NP_000050.3:p.(Ile3312Val), also p.(I3312V).The recorded REVEL score is 0.017.The published ClinGen SVI REVEL calibration assigns BP4 supporting at REVEL <=0.29 (Pejaver et al. 2022, PMID:36413997).

cspec ↗

Assessed · not applied · 5 not met · 11 not assessed

Pathogenic

PS1 Not assessed: no governing-VCEP entry or established pathogenic comparator for p.Ile3312Val was identified in the searched files.

PS3 Not assessed: no variant-specific protein-function assay or pre-assigned PS3 code was found in the governing ENIGMA materials.

PS4 Not assessed: no exact-variant case-control odds ratio, p-value, and confidence interval were available for PS4 (p-value <=0.05 and OR >=4).

PM2 Not assessed: required non-cancer absence and depth data are unavailable; all-comers gnomAD reports 4/251266 alleles in v2.1 and 22/1614244 in v4.1.

PM3 Not assessed: the exact-variant report documents heterozygosity but no Fanconi-anemia phenotype, second pathogenic BRCA2 variant, or phase needed for ENIGMA PM3 points.

PP1 Not assessed: no segregation LR or tested affected relatives were reported, so the ENIGMA PP1 threshold of LR >=2.08 cannot be evaluated.

PP3 Not met: REVEL 0.017 is below the PP3 supporting threshold of 0.644 for missense variants.

PP4 Not met: exact-variant clinical-history LR 0.7815407011846 >= 2.08? no, so it does not reach the ENIGMA PP4 Supporting threshold.

PP5 Not met: ClinVar has zero exact-variant expert-panel submissions, and no expert-panel Pathogenic or Likely pathogenic classification is present.

Benign

BA1 Not assessed: required non-cancer FAF data are unavailable; available all-comers group-max FAF values were 7.02e-06 and 8.78e-06 versus the >0.001 BA1 threshold.

BS1 Not assessed: required non-cancer FAF data are unavailable; available all-comers group-max FAF values were 7.02e-06 and 8.78e-06 versus the >0.00002 BS1 threshold.

BS2 Not assessed: gnomAD reports 0 homozygotes, but no phenotype-qualified biallelic observations or ENIGMA BS2 point assignments are available.

BS3 Not assessed: no variant-specific protein-function assay or pre-assigned BS3 code was found in the governing ENIGMA materials.

BS4 Not assessed: no non-segregation LR or tested discordant affected relatives were reported, so the ENIGMA BS4 threshold of LR <=0.48 cannot be evaluated.

BP5 Not met: exact-variant clinical-history LR 0.7815407011846 <= 0.48? no, so it does not reach the ENIGMA BP5 Supporting threshold.

BP6 Not met: ClinVar has zero exact-variant expert-panel submissions, so no expert-panel Benign or Likely benign classification supports BP6.

N/A · 10 PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · BP2 · BP3 · BP7

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.36287e-05; MAF= 0.00136%, 22/1614244 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 3.19939e-05; MAF= 0.00320%, 2/62512 alleles, homozygotes = 0); grpmax FAF= 8.78e-06.

v2.1

This variant is present in gnomAD v2.1 (AF= 1.59194e-05; MAF= 0.00159%, 4/251266 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000163026; MAF= 0.01630%, 1/6134 alleles, homozygotes = 0); grpmax FAF= 7.02e-06.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0014% · 22 / 1,614,244
0 hom · FAF 0.00088%

Remaining individuals 2 / 62,512	0.0032%
East Asian 1 / 44,890	0.0022%
South Asian 2 / 91,086	0.0022%
European (non-Finnish) 17 / 1,180,044	0.0014%

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

gnomAD v2.1

0.0016% · 4 / 251,266
0 hom · FAF 0.0007%

Remaining individuals 1 / 6,134	0.016%
European (non-Finnish) 3 / 113,608	0.0026%

+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), 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 Uncertain significance (9 clinical laboratories) and as Likely benign (2 clinical laboratories) and as Likely Benign (1 clinical laboratory). (ClinVarID = 38265)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.017. BayesDel score = -0.72086.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA2, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.

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

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

23918944 ↗ Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. CLINVAR

24817641 ↗ An integrated in silico approach to analyze the involvement of single amino acid polymorphisms in FANCD1/BRCA2-PALB2 and FANCD1/BRCA2-RAD51 complex. CLINVAR

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

27403073 ↗ BRCA1 and BRCA2 sequence variations detected with next-generation sequencing in patients with premature ovarian insufficiency. CLINVAR

28422718 ↗ Validation and optimization of the Ion Torrent S5 XL sequencer and Oncomine workflow for BRCA1 and BRCA2 genetic testing. CLINVAR

33773534 ↗ Next Generation Sequencing-Based Germline Panel Testing for Breast and Ovarian Cancers in Pakistan. CLINVAR

39451174 ↗ The relationship between mutation carriage of BRCA1/2 and clinicopathological characteristics in women with breast cancer - experience from a diagnostic centre in Turkey. CLINVAR

17392385 ↗ American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CLINVAR

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