Classification rationale

PM2 BP1 Likely Benign

BRCA2 c.3270G>C missense · exon 11

Likely Benign: BP1 (strong) because p.Met1090Ile lies outside BRCA2's clinically important functional domains (aa 10-40 and aa 2481-3186) with SpliceAI max delta 0.00. Likely Benign: PM2 (supporting) because the variant is absent from the VCEP-specified gnomAD v2.1 non-cancer exome and gnomAD v3.1 non-cancer control sources.

PM2 + BP1 → 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

PM2 supporting Pathogenic

Met at Supporting: absent from both VCEP-specified control sources, gnomAD v2.1 non-cancer exome and gnomAD v3.1 non-cancer, versus the PM2_Supporting absence rule.

ENIGMA specification v1.2, PM2 (default assigned weight: Supporting): 'Absent from controls in an outbred population, from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer). Region around the variant must have an average read depth >=25. See Appendix G for details.'ENIGMA specification v1.2 instructions for PM2: 'Observation of a variant only once in a gnomAD outbred population is not informative. Do not apply for insertion, deletion or delins variants. Do not apply if read depth <25 at region around the variant.' This variant is a single-nucleotide substitution, so the indel exclusion does not apply.Appendices v1.2, Appendix G: absent-in-controls calibrated to PM2_Supporting (175/609 likely-benign vs 116/140 likely-pathogenic variants, LR 2.88, 95% CI 2.49-3.34); read depth >25 recommended for PM2_Supporting.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

BP1 strong Benign

Met, strong: missense at residue 1090 lies outside BRCA2's clinically important domains (aa 10-40, aa 2481-3186) with SpliceAI max delta 0.0 (<=0.1).

ENIGMA Table 1 (Specifications v1.2) and Appendix J Table 16 direct that BP1_Strong be applied for silent, missense or in-frame insertion/deletion variants outside a (potentially) clinically important functional domain with no splicing predicted (SpliceAI <= 0.1).ENIGMA Appendix C (Table 4) and Appendix J define the (potentially) clinically important BRCA2 functional domains as PALB2 binding aa 10-40 and DNA binding aa 2481-3186; residue 1090 (Met1090Ile) is outside both, and Appendix C notes the additional conserved region aa 1103-1183 with no pathogenic missense substitutions recorded.The case evidence reports SpliceAI maximum delta 0.00 for c.3270G>C, satisfying the SpliceAI <= 0.1 no-splicing condition of BP1_Strong.

cspec ↗spliceai ↗PMID:31911673 ↗

Assessed · not applied · 13 not met · 3 not assessed

Pathogenic

PS1 Not met: no pathogenic variant producing p.Met1090Ile via a different nucleotide change exists; ClinVar lists only conflicting VUS/likely-benign submissions for this change.

PS3 Not met: no calibrated damaging-effect functional assay for p.Met1090Ile appears in the ENIGMA v1.2 Table 9 curated results.

PS4 Not met: no case-control odds ratio exists for this variant to test against the ENIGMA PS4 threshold of OR >=4.0.

PM3 Not met: no BRCA2-related Fanconi Anemia proband with a co-occurring BRCA2 pathogenic variant was found, yielding 0 of the >=2 PM3 points required.

PP1 Not assessed: no family pedigree or co-segregation likelihood ratio for c.3270G>C exists, so the ENIGMA PP1 thresholds (supporting LR>=2.08) cannot be evaluated.

PP3 Not met: p.Met1090Ile lies outside BRCA2's functional domains and its BayesDel no-AF score of -0.50 is far below the ENIGMA BRCA2 PP3 threshold of >=0.30.

PP4 Not met: no variant-level combined clinical likelihood ratio exists for this variant to test against the PP4 threshold of LR >=2.08.

PP5 Not met: ClinVar has no expert-panel classification for this variant (1 star, six single-laboratory submissions, 0 expert panels).

Benign

BA1 Not met: absent from gnomAD v2.1 non-cancer exome and v3.1 non-cancer, and the v4.1 all-comers AF of 1.26e-06 is far below the 0.001 BA1 threshold.

BS1 Not met: absent from the VCEP-specified gnomAD v2.1 non-cancer exome and v3.1 non-cancer sources, versus the >0.00002 BS1_Supporting threshold.

BS2 Not assessed: no proband co-occurrence or age-at-diagnosis data; gnomAD shows zero homozygotes, which Appendix H bars from BS2 application.

BS3 Not met: no calibrated assay showing normal protein function for p.Met1090Ile is listed in the ENIGMA v1.2 Table 9 curated results.

BS4 Not assessed: no non-segregation likelihood ratio is available; the BS4-governing ENIGMA posterior-probability file could not be converted and no variant row was found in any searched table.

BP4 Not met: the ENIGMA BRCA2 BP4 missense rule requires location inside a clinically important functional domain, and p.Met1090Ile lies outside both domains.

BP5 Not met: no variant-level combined clinical likelihood ratio exists for this variant to test against the BP5 threshold of LR <=0.48.

BP6 Not met: the two Likely benign ClinVar submissions are ordinary laboratories, not an expert panel (0 expert panels, 1 star).

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= 1.25912e-06; MAF= 0.00013%, 2/1588408 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 3.26435e-05; MAF= 0.00326%, 2/61268 alleles, homozygotes = 0).

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00013% · 2 / 1,588,408
0 hom

Remaining individuals

2 / 61,268

0.0033%

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

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

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 (3 clinical laboratories) and as Likely benign (2 clinical laboratories). (ClinVarID = 51441)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.319. BayesDel score = -0.499525.

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 ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 8 further PMIDs triaged but not cited — see Sources & references.

Rule & framework references · cited for criterion definitions, not variant evidence

31911673 ↗ Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots".

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

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

31672839 ↗ Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. CLINVAR

12692171 ↗ American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. CLINVAR

24366402 ↗ Summaries for patients. Assessing the genetic risk for BRCA-related breast or ovarian cancer in women: recommendations from the U.S. Preventive Services Task Force. CLINVAR

26389258 ↗ Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Versi CLINVAR

35264596 ↗ Detection of germline variants in Brazilian breast cancer patients using multigene panel testing. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

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