Variant classification summary

NM_000059.4:c.3270G>C

BRCA2 · NP_000050.3:p.(Met1090Ile) · NM_000059.4

GRCh37: chr13:32911762 G>C · GRCh38: chr13:32337625 G>C

Gene: BRCA2 Transcript: NM_000059.4

Final call

Likely Benign

BP1 strong PM2 supporting

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Met1090Ile)

gnomAD AF

1.2591223413631762e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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.

Final determination: Under the ENIGMA BRCA2 VCEP Version 1.2 conflicting-evidence point system, BP1 strong is -4 points and PM2 supporting is +1 point; the total of -3 falls within the Likely Benign range of -6 to -2.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Not applicable: p.Met1090Ile is a missense substitution, outside the ENIGMA PVS1 null-variant decision tree, and SpliceAI max delta 0.00 excludes any RNA-level loss of function.	cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18 spliceai
PS1	Not met	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.	cspec vcep_specifications_v1_2_2024_11_18 clinvar
PS2	N/A	Not applicable: ENIGMA BRCA2 v1.2 declares PS2 inapplicable because BRCA2-related cancers are common and de novo occurrence predictive capacity is uncalibrated.	cspec vcep_specifications_v1_2_2024_11_18
PS3	Not met	Not met: no calibrated damaging-effect functional assay for p.Met1090Ile appears in the ENIGMA v1.2 Table 9 curated results.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18 oncokb PMID:31911673
PS4	Not met	Not met: no case-control odds ratio exists for this variant to test against the ENIGMA PS4 threshold of OR >=4.0.	cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001 clinvar gnomad_v2 gnomad_v4
PM1	N/A	Not applicable: ENIGMA designates PM1 'do not use' for BRCA2, incorporating domain information into the calibrated bioinformatic codes BP1, BP4 and PP3 instead.	cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM2	Met	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.	cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 gnomad_v2 gnomad_v4
PM3	Not met	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.	cspec vcep_specifications_v1_2_2024_11_18 clinvar
PM4	N/A	Not applicable: ENIGMA BRCA2 v1.2 retires PM4 ('do not use') and p.Met1090Ile is a missense substitution, which by definition causes no protein-length change.	cspec vcep_specifications_v1_2_2024_11_18
PM5	N/A	Not applicable: ENIGMA retires classic missense PM5 for BRCA2, repurposing it as exon-weighted PM5(PTC) for truncating variants only; this is a missense change.	cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18 pm5_candidates
PM6	N/A	Not applicable: ENIGMA BRCA2 v1.2 declares PM6 inapplicable, since BRCA2-related cancers are common and assumed de novo evidence is uncalibrated.	cspec vcep_specifications_v1_2_2024_11_18
PP1	Not assessed	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.	cspec vcep_specifications_v1_2_2024_11_18 vcep_humu_40_1557_s001
PP2	N/A	Not applicable: ENIGMA excludes PP2 for BRCA2 because missense variants are not a common mechanism of pathogenicity for this gene.	cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PP3	Not met	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.	cspec bayesdel spliceai revel vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PP4	Not met	Not met: no variant-level combined clinical likelihood ratio exists for this variant to test against the PP4 threshold of LR >=2.08.	cspec vcep_specifications_v1_2_2024_11_18 vcep_pmid_31853058_brca2_clinical_history_lr vcep_pmid_31853058_li_2020_geneticsinmedicine vcep_humu_40_1557_s001 vcep_pmid_17924331_easton_2007_ajhg
PP5	Not met	Not met: ClinVar has no expert-panel classification for this variant (1 star, six single-laboratory submissions, 0 expert panels).	cspec clinvar
BA1	Not met	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.	cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 gnomad_v2 gnomad_v4
BS1	Not met	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.	cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no proband co-occurrence or age-at-diagnosis data; gnomAD shows zero homozygotes, which Appendix H bars from BS2 application.	cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
BS3	Not met	Not met: no calibrated assay showing normal protein function for p.Met1090Ile is listed in the ENIGMA v1.2 Table 9 curated results.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18 PMID:31911673
BS4	Not assessed	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.	cspec vcep_specifications_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
BP1	Met	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).	cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 spliceai PMID:31911673
BP2	N/A	Not applicable: the ENIGMA BRCA2 v1.2 specification restricts BP2 to the BS2 context, and no in-trans/in-cis co-occurrence data exists for this variant.	cspec vcep_specifications_v1_2_2024_11_18
BP3	N/A	Not applicable: ENIGMA BRCA2 v1.2 retires BP3 ('do not use') and p.Met1090Ile is a missense substitution, not an in-frame indel in a repeat region.	cspec vcep_specifications_v1_2_2024_11_18
BP4	Not met	Not met: the ENIGMA BRCA2 BP4 missense rule requires location inside a clinically important functional domain, and p.Met1090Ile lies outside both domains.	cspec bayesdel spliceai revel vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 PMID:31911673
BP5	Not met	Not met: no variant-level combined clinical likelihood ratio exists for this variant to test against the BP5 threshold of LR <=0.48.	cspec vcep_specifications_v1_2_2024_11_18 vcep_pmid_31853058_brca2_clinical_history_lr vcep_humu_40_1557_s001 vcep_pmid_17924331_easton_2007_ajhg clinvar
BP6	Not met	Not met: the two Likely benign ClinVar submissions are ordinary laboratories, not an expert panel (0 expert panels, 1 star).	cspec clinvar
BP7	N/A	Not applicable: BP7 covers only synonymous (or qualifying intronic) variants, and c.3270G>C is a missense substitution (p.Met1090Ile).	cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18

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