Variant classification summary

NM_000059.4:c.*23A>C

BRCA2 · NP_000050.3:p.? · NM_000059.4

GRCh37: chr13:32972930 A>C · GRCh38: chr13:32398793 A>C

Gene: BRCA2 Transcript: NM_000059.4

Final call

VUS

BP4 supporting

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.?

gnomAD AF

1.8615087155838063e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000059.4:c.*23A>C is a 3' UTR substitution in BRCA2 exon 27, downstream of the stop codon. SpliceAI predicts no splicing impact (max delta = 0.00) and the variant is outside the clinically important PALB2-binding and DNA-binding domains.

2

The variant is present at very low frequency in gnomAD (v2.1: 1/31406 genome alleles, 0.00318%; v4.1: 3/1611596 alleles, FAF=2.8e-7) and is absent from gnomAD-Canada. These frequencies are below the ENIGMA BA1 and BS1 thresholds.

3

This variant has been reported in ClinVar (Variation ID 438948) as Uncertain significance by a single clinical laboratory (1-star review status). Three papers cited in the ClinVar submission (PMID:29208711 on polyadenylation signal recognition, PMID:29648582 on polyadenylation code inference, PMID:26467025 on DNA variant scoring) discuss polyadenylation biology and variant interpretation methodology but do not mention BRCA2 or NM_000059.4:c.*23A>C.

4

BP4 (supporting) is met: computational evidence (SpliceAI) predicts no splicing impact. No pathogenic, likely pathogenic, or benign criteria beyond BP4 are met given the absence of functional, clinical, segregation, or case-control data specific to this 3' UTR variant.

Final determination: ENIGMA BRCA2 v1.2 Table 3: no benign or likely benign combination is satisfied by a single BP4 (Supporting Benign) criterion alone; points-based scoring yields -1 which falls in the Uncertain Significance range (-1 to 5).

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	Not met	NM_000059.4:c.*23A>C is a 3' UTR substitution, not a null variant (nonsense, frameshift, or canonical ±1,2 splice site). PVS1 requires a loss-of-function variant type. The generic PVS1 assessment confirms this variant does not fall into any PVS1-eligible bucket.	pvs1_gene_context pvs1_variant_assessment
PS1	N/A	Not a missense variant and no predicted splicing impact. No same amino acid change comparator exists for a 3' UTR substitution.
PS2	N/A	ENIGMA BRCA2 CSPEC declares PS2 Not Applicable.	cspec
PS3	Not met	No functional studies test NM_000059.4:c.*23A>C or a systematically characterized range that includes this 3' UTR position. Not listed in ENIGMA Specifications Table 9 for curated functional assay results. The three papers cited in the ClinVar submission (PMID:29208711, 29648582, 26467025) are polyadenylation methodology papers that do not mention BRCA2 or this variant.	vcep_specifications_table9_v1_2_2024_11_18 PMID:29208711 PMID:29648582 PMID:26467025
PS4	Not met	No case-control data comparing variant prevalence in affected versus unaffected individuals is available for this variant.
PS5	N/A	ENIGMA BRCA2 CSPEC declares PS5 Not Applicable for this VCEP. ClinVar review status is 1-star (criteria provided, single submitter) — does not meet the 3-star expert panel threshold for global PP5 override.	cspec clinvar
PM1	N/A	ENIGMA BRCA2 CSPEC considers PM1 as a component of bioinformatic analysis (PP3/BP4) and declares it Not Applicable as a standalone criterion.	cspec
PM2	Not met	Variant is present in gnomAD v2.1 (1/31406 genome alleles, AF=3.18e-5) and gnomAD v4.1 (3/1611596 alleles, AF=1.86e-6). ENIGMA PM2_Supporting requires absence from gnomAD v2.1 exome-only subset and v3.1 non-cancer. While absent from the exome-only subset (0/0, region may not be captured by exome), a single observation in an outbred population is explicitly stated as not informative for PM2 per ENIGMA guidance.	gnomad_v2 gnomad_v4 cspec
PM5	N/A	ENIGMA PM5 is repurposed for protein termination codon (PTC) variants where a different proven pathogenic PTC has been seen in the same exon. This is a 3' UTR substitution, not a PTC variant. PM5 candidates analysis confirms not_applicable.	pm5_candidates cspec
PM6	N/A	ENIGMA BRCA2 CSPEC declares PM6 Not Applicable.	cspec
PP1	Not met	No co-segregation data or likelihood ratio analysis available for this variant. ENIGMA PP1 requires a quantitative co-segregation LR ≥ 2.08.
PP2	N/A	ENIGMA BRCA2 CSPEC declares PP2 Not Applicable.	cspec
PP3	Not met	SpliceAI predicts no splicing impact (max delta = 0.0). The variant is a 3' UTR substitution, not a missense/in-frame change, so BayesDel is not applicable. ENIGMA PP3 requires either BayesDel no-AF ≥ 0.30 (for missense/in-frame in clinically important domain) or SpliceAI ≥ 0.2 (for predicted splicing impact). Neither condition is met.	spliceai cspec
PP4	Not met	Variant not found in the ENIGMA clinical history likelihood ratio table (PMID:31853058 BRCA2 clinical_history_LR.xlsx). No LR data available to support PP4. ENIGMA PP4 requires LR ≥ 2.08 from calibrated multifactorial likelihood clinical data.	vcep_pmid_31853058_brca2_clinical_history_lr
PP5	N/A	ENIGMA BRCA2 CSPEC declares PP5 Not Applicable for this VCEP. ClinVar review status is 1-star (criteria provided, single submitter) — does not meet the 3-star expert panel threshold for global PP5 override.	cspec clinvar
BA1	Not met	Filtering allele frequency (FAF) of 2.8e-7 in gnomAD v4.1 is well below the ENIGMA BA1 threshold of 0.1% (FAF > 0.001). BA1 stand-alone benign criterion is not triggered.	gnomad_v4 cspec
BS1	Not met	Filtering allele frequency (FAF) of 2.8e-7 in gnomAD v4.1 is below both the ENIGMA BS1_Strong threshold (FAF > 0.0001) and BS1_Supporting threshold (FAF > 0.00002). The variant is too rare in population databases to satisfy BS1.	gnomad_v4 cspec
BS2	Not met	No co-occurrence data with pathogenic variants in trans is available. ENIGMA BS2 requires observation in healthy adults without Fanconi Anemia phenotype, assessed via a points system (Specifications Table 8). No proband data available for this variant.
BS3	Not met	Not listed in ENIGMA Specifications Table 9 for curated functional assay results. No published functional studies demonstrate no damaging effect on protein function or splicing for this variant.	vcep_specifications_table9_v1_2_2024_11_18
BS4	Not met	No segregation data demonstrating lack of segregation in affected family members is available. ENIGMA BS4 requires quantitative co-segregation analysis with LR ≤ 0.48.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease. This is a 3' UTR substitution, not a missense variant. The ENIGMA BP1_Strong rule covers silent substitutions, missense, and in-frame variants — 3' UTR substitutions are not enumerated.	cspec
BP2	N/A	ENIGMA BRCA2 CSPEC declares BP2 Not Applicable.	cspec
BP4	Met	This 3' UTR substitution has no predicted impact on mRNA splicing (SpliceAI max delta = 0.00). The variant is located in exon 27, outside the native donor/acceptor splice sites, and outside the ENIGMA-defined clinically important functional domains (PALB2 binding aa 10-40; DNA binding aa 2481-3186). Per ENIGMA Figure 1A, variants with no predicted splicing impact and no protein-level impact receive BP4 at supporting strength.	spliceai cspec
BP5	Not met	Variant not found in the ENIGMA clinical history likelihood ratio table (PMID:31853058 BRCA2 clinical_history_LR.xlsx). No LR data available to support BP5. ENIGMA BP5 requires LR ≤ 0.48 from calibrated multifactorial likelihood clinical data.	vcep_pmid_31853058_brca2_clinical_history_lr
BP6	N/A	ENIGMA BRCA2 CSPEC declares BP6 Not Applicable. ClinVar review status is 1-star (criteria provided, single submitter) — does not meet the 3-star expert panel threshold for global BP6 override.	cspec clinvar
BP7	Not met	ENIGMA BP7 requires either mRNA assay data demonstrating no damaging effect on splicing (BP7_Strong RNA), or application to silent/intronic variants at specific positions with BP4 already met. This is a 3' UTR substitution — not a silent coding variant and not an intronic variant at the positions specified by ENIGMA. No mRNA splicing assay data is available.	cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.