Variant classification summary

NM_000059.4:c.3417G>A

BRCA2 · NP_000050.3:p.(Lys1139=) · NM_000059.4

GRCh37: chr13:32911909 G>A · GRCh38: chr13:32337772 G>A

Gene: BRCA2 Transcript: NM_000059.4

Final call

Likely Benign

BP1 strong benign BP6 supporting benign

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Lys1139=)

gnomAD AF

0.00010038157390872217 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000059.4:c.3417G>A (p.Lys1139=) is a synonymous substitution in BRCA2 exon 11, located outside both clinically important functional domains defined by ENIGMA (aa 10-40 PALB2 binding and aa 2481-3186 DNA binding).

2

BP1_Strong is met: silent substitution outside a clinically important functional domain with no predicted splicing impact (SpliceAI max delta = 0.00).

3

The variant is present in gnomAD v2.1 (40/250,942 alleles, AF=0.000159) and v4.1 (162/1,613,842 alleles, AF=0.000100), with highest frequency in the Ashkenazi Jewish population (AF=0.00357), consistent with a founder effect. The grpmax filter allele frequency (FAF=2.93e-06 v2.1, FAF=1.88e-05 v4.1) does not meet ENIGMA BS1 thresholds.

4

The variant has been classified as Likely benign by the ENIGMA expert panel in ClinVar (Variation ID 135796, 3-star review status), with 8 clinical laboratories reporting Likely benign, 3 reporting Benign, and 1 reporting Likely Benign.

5

No variant-specific functional assay data, segregation analysis, case-control data, or clinical-history likelihood ratios were identified for this variant in the ENIGMA curated datasets (Table 9, HUMU, clinical_history_LR, ST7) or in the reviewed literature.

6

No publication among the 8 PMIDs reviewed (20104584, 25741868, 23918944, 23788249, 17392385, 18163131, 20301425, 28492532) contained a specific mention of NM_000059.4:c.3417G>A.

Final determination: One Strong Benign criterion (BP1) plus one Supporting Benign criterion (BP6) yields Likely Benign per ENIGMA Table 3 combination rules.

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	NM_000059.4:c.3417G>A is a synonymous substitution (NP_000050.3:p.Lys1139=) and does not fall into any ENIGMA PVS1 null-variant category (nonsense, frameshift, canonical splice site, initiation codon, or exon deletion).	pvs1_variant_assessment
PS1	N/A	PS1 under ENIGMA v1.2 applies to missense substitutions with a previously classified pathogenic comparator at the same residue, or to splice-impact variants with same predicted splicing outcome as a known pathogenic variant. This variant is synonymous with SpliceAI delta = 0.00, so neither pathway applies.
PS2	N/A	ENIGMA v1.2 explicitly designates PS2 as not applicable for this VCEP.	cspec
PS3	Not assessed	No variant-specific functional assay data were identified in the ENIGMA curated functional assay table (Specifications Table 9), the HUMU multifactorial dataset, or any reviewed publication. The variant is not listed in any calibrated BRCA2 functional study.	vcep_specifications_table9_v1_2_2024_11_18 vcep_humu_40_1557_s001
PS4	Not assessed	No case-control study with variant-specific odds ratio and p-value meeting ENIGMA PS4 thresholds (p ≤ 0.05, OR ≥ 4, lower CI excludes 2.0) was identified. The WECARE study (PMID:20104584) compared aggregated VUS groups but did not provide variant-level case-control data for c.3417G>A.	PMID:20104584
PS5	N/A	PS5 is not part of the ENIGMA BRCA2 VCEP v1.2 framework; this criterion is not defined in the CSPEC ruleset.	cspec
PM1	N/A	ENIGMA v1.2 designates PM1 as not applicable; domain-level analysis is captured through the bioinformatic code application flowchart (PP3/BP4) instead.	cspec
PM2	Not met	PM2_Supporting under ENIGMA requires absence from gnomAD v2.1 (non-cancer, exome only) and gnomAD v3.1 (non-cancer) outbred populations. This variant is present in gnomAD v2.1 at AF=0.000159 (40/250,942 alleles) and in gnomAD v4.1 at AF=0.000100 (162/1,613,842 alleles), so the absence criterion is not satisfied.	gnomad_v2 gnomad_v4
PM5	N/A	ENIGMA PM5 is repurposed as PM5_PTC for protein termination codon variants only. This variant is synonymous (K1139=), not a PTC, and the pm5_candidates assessment confirmed PM5 is not applicable via either classic same-residue missense or PTC pathways.	pm5_candidates
PM6	N/A	ENIGMA v1.2 explicitly designates PM6 as not applicable for this VCEP.	cspec
PP1	Not assessed	No co-segregation data or LR analysis meeting ENIGMA PP1 thresholds (LR ≥ 2.08) were identified for this variant. No variant-specific segregation analysis was found in the reviewed publications or VCEP reference datasets.
PP2	N/A	ENIGMA v1.2 explicitly designates PP2 as not applicable for this VCEP.	cspec
PP3	Not met	ENIGMA PP3 requires either (a) missense/in-frame variant inside a clinically important functional domain with BayesDel no-AF score ≥ 0.30, or (b) SpliceAI delta ≥ 0.20 for silent/missense/intronic variants. This variant is synonymous, located outside BRCA2 clinically important functional domains (aa 10-40 and aa 2481-3186), and SpliceAI max delta is 0.00. Neither pathway is satisfied.	spliceai cspec
PP4	Not assessed	No variant-specific clinical-history likelihood ratio meeting ENIGMA PP4 thresholds (LR ≥ 2.08) was identified. The variant was not found in the Li et al. 2020 (PMID:31853058) BRCA2 clinical_history_LR spreadsheet.	vcep_pmid_31853058_brca2_clinical_history_lr
PP5	Not met	The ENIGMA expert panel has classified this variant as Likely benign in ClinVar (Variation ID 135796, review status: reviewed by expert panel). PP5 is a pathogenic criterion requiring a reputable source to have classified the variant as pathogenic; the expert panel classification is benign-direction, not pathogenic.	clinvar
BA1	Not met	ENIGMA BA1 (Stand Alone benign) requires filter allele frequency (FAF) > 0.001 (0.1%) in gnomAD non-founder populations. The grpmax FAF is 2.93e-06 (v2.1) and 1.88e-05 (v4.1), both well below the BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	ENIGMA BS1_Strong requires FAF > 0.0001 and BS1_Supporting requires FAF > 0.00002 in gnomAD non-founder populations. The grpmax FAF is 2.93e-06 (gnomAD v2.1) and 1.88e-05 (gnomAD v4.1), both below the BS1_Supporting threshold of 0.00002. The elevated Ashkenazi Jewish frequency (AF=0.00357) is attributable to a known founder effect and is excluded by the FAF adjustment.	gnomad_v2 gnomad_v4
BS2	Not assessed	ENIGMA BS2 requires assessment of observed homozygotes or compound heterozygotes for absence of Fanconi Anemia phenotype, using a points-based system (Specifications Table 8). No variant-specific proband data with FA phenotype assessment were identified. gnomAD v2.1 reports 0 homozygotes out of 250,942 alleles.	gnomad_v2
BS3	Not assessed	No variant-specific functional assay data showing no damaging effect on protein function were identified. The variant is absent from ENIGMA Table 9 (curated BS3 assignments) and the HUMU SuppT4 functional assay dataset. No publication with variant-specific functional data was found.	vcep_specifications_table9_v1_2_2024_11_18 vcep_humu_40_1557_s001
BS4	Not assessed	No variant-specific lack-of-segregation LR analysis meeting ENIGMA BS4 thresholds (LR ≤ 0.48) was identified. The variant was not found in the ENIGMA Supplementary Table ST7 reference set or the HUMU multifactorial dataset.	vcep_supplementarytables_v1_2_2024_11_18 vcep_humu_40_1557_s001
BP1	Met	BP1_Strong applies under ENIGMA v1.2: c.3417G>A is a silent substitution (p.Lys1139=) located at residue 1139, which is outside both BRCA2 clinically important functional domains (PALB2 binding domain aa 10-40 and DNA binding domain aa 2481-3186). SpliceAI predicts no splicing impact (max delta = 0.00, ≤ 0.1). Both conditions for BP1_Strong are satisfied.	cspec spliceai
BP2	N/A	ENIGMA v1.2 explicitly designates BP2 as not applicable for this VCEP.	cspec
BP4	N/A	ENIGMA BP4 applies only to missense, in-frame, or silent variants inside a clinically important functional domain with no predicted impact. Residue K1139 is outside both BRCA2 clinically important functional domains (PALB2 binding aa 10-40 and DNA binding aa 2481-3186), so BP4 does not apply.	cspec
BP5	Not assessed	No variant-specific clinical-history likelihood ratio meeting ENIGMA BP5 thresholds (LR ≤ 0.48) was identified. The variant was not found in the Li et al. 2020 (PMID:31853058) BRCA2 clinical_history_LR spreadsheet.	vcep_pmid_31853058_brca2_clinical_history_lr
BP6	Met	Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Likely benign.	cspec clinvar
BP7	N/A	ENIGMA BP7_Supporting requires a silent variant inside a clinically important functional domain with BP4 met. BP7_Strong (RNA) requires well-established mRNA assay data showing no damaging effect. K1139 is outside the functional domains, BP4 is not met, and no variant-specific RNA assay data were identified.	cspec
BP3	N/A	ENIGMA v1.2 designates BP3 as not applicable; captured by bioinformatic tool prediction and domain analysis.	cspec
PM3	N/A	Skipped per user directive: not applicable for this variant type (synonymous substitution in BRCA2 without Fanconi Anemia phenotype data).
PM4	N/A	Skipped per user directive: NM_000059.4:c.3417G>A is a substitution, not an in-frame deletion/insertion or stop-loss variant.

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