Variant classification summary

NM_000059.4:c.7977-15T>G

BRCA2 · NP_000050.3:p.? · NM_000059.4

GRCh37: chr13:32937301 T>G · GRCh38: chr13:32363164 T>G

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

1.2467491017172721e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000059.4:c.7977-15T>G is an intronic substitution located 15 bases upstream of BRCA2 exon 18, outside the canonical acceptor splice site consensus (+/-1,2). SpliceAI predicts no significant impact on splicing (max delta = 0.03), supporting a benign bioinformatic assessment under ENIGMA BP4_Supporting.

2

This variant is extremely rare in population databases, present in 2 of 1,604,172 alleles in gnomAD v4.1 (AF = 1.25e-06), both in the European non-Finnish population. It is absent from gnomAD v2.1. The FAF of 2.8e-07 does not meet ENIGMA BS1 thresholds for benign population evidence, nor does it meet BA1 stand-alone benign criteria.

3

In a multifactorial likelihood analysis by Parsons et al. 2019 (PMID:31131967), this variant had a combined likelihood ratio of 1.11 (co-occurrence LR = 1.02; family history LR = 1.08), which falls within the neutral zone and does not provide evidence for either pathogenicity (PP4) or benignity (BP5).

4

The variant has been reported in ClinVar as Likely benign by 4 clinical laboratories and as Uncertain significance by 2 laboratories (ClinVar ID: 96863), though no expert panel classification has been assigned.

5

The adjacent canonical splice acceptor variant c.7977-1G>C is a well-established pathogenic variant (Parsons et al. 2019 posterior probability = 0.999; IARC Class 5), but c.7977-15T>G does not disrupt the splice consensus and is predicted to be splicing-neutral by SpliceAI.

6

Overall, only BP4_Supporting is met. Under the ENIGMA Table 3 combining rules, a single supporting benign criterion does not reach the threshold for Likely Benign (which requires either Strong_benign + Supporting_benign or >= 2 Supporting_benign). This variant is classified as a Variant of Uncertain Significance (VUS).

Final determination: A single Supporting_benign criterion (BP4_Supporting) does not meet any ENIGMA Table 3 Likely Benign combination (requires >=2 Supporting_benign or 1 Strong/Moderate_benign + 1 Supporting_benign), and falls in the VUS range (-1 to 5) under the ENIGMA point system.

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	Intronic variant at c.7977-15, 15 bases upstream of exon 18 acceptor site. Not a canonical +/-1,2 splice consensus variant. Does not meet the ENIGMA PVS1 definition of a null variant (nonsense, frameshift, canonical splice site, initiation codon, or exon deletion). No mRNA assay data suggestive of a damaging splicing effect (SpliceAI max delta = 0.03).	cspec spliceai pvs1_generic_framework
PS1	Not met	No previously classified pathogenic or likely pathogenic variant identified at the c.7977-15 position with the same predicted splicing effect. No comparator variant found in ENIGMA VCEP materials or ClinVar expert panel submissions.	cspec clinvar vcep_specifications_table4_v1_2_2024_11_18
PS2	N/A	ENIGMA BRCA2 VCEP specification marks PS2 as Not Applicable.	cspec
PS3	Not met	Not listed in ENIGMA Specifications Table 9 (curated functional assay results for BRCA2). No functional assay data demonstrating a damaging effect on protein function or splicing for this intronic variant. The adjacent canonical splice variant c.7977-1G>C is pathogenic, but the -15 position has no functional evidence.	vcep_specifications_table9_v1_2_2024_11_18 cspec
PS4	Not met	No case-control study data available. Not listed in ENIGMA ST7 reference set. Variant absent from COSMIC. ClinVar submissions do not include PS4-level case-control evidence. Published literature reviewed consists of clinical practice guidelines and policy statements with no variant-specific case data.	vcep_supplementarytables_v1_2_2024_11_18 clinvar
PS5	N/A	ENIGMA BRCA2 VCEP specification marks PS5 as Not Applicable.	cspec
PM1	N/A	ENIGMA VCEP specification states PM1 is considered as a component of bioinformatic analysis (PP3/BP4) rather than an independent criterion.	cspec
PM2	Not met	Under ENIGMA PM2_Supporting, the variant must be absent from both gnomAD v2.1 (non-cancer, exome only) and gnomAD v3.1 (non-cancer). The variant is absent from gnomAD v2.1 but is present in gnomAD v3.1/v4.1 with 1 genome allele and 2 total alleles (all in European non-Finnish, an outbred population). Additionally, ENIGMA states a single observation in an outbred population is not informative; here there are 2 observations. The variant does not meet the strict 'absent from both' requirement.	gnomad_v2 gnomad_v4 cspec
PM5	N/A	ENIGMA PM5 is repurposed for protein termination codon (PTC) logic (PM5_PTC). This intronic substitution at -15 is not a PTC variant. Classic same-residue missense PM5 is not applicable to intronic variants.	cspec pm5_candidates
PM6	N/A	ENIGMA BRCA2 VCEP specification marks PM6 as Not Applicable.	cspec
PP1	Not met	No co-segregation data available. The variant was included in the Easton et al. 2007 dataset with 1 family history score entry (SuppT2 of Parsons et al. 2019), but no quantitative co-segregation LR has been calculated. The ENIGMA PP1 rule requires LR >= 2.08 for supporting evidence.	vcep_humu_40_1557_s001 cspec
PP2	N/A	ENIGMA BRCA2 VCEP specification marks PP2 as Not Applicable.	cspec
PP3	Not met	ENIGMA PP3 for intronic variants outside donor/acceptor +/-1,2 positions requires SpliceAI delta >= 0.2. The SpliceAI max delta score for this variant is 0.03, well below the threshold. This is an intronic variant, not a missense substitution, so the BayesDel protein prediction pathway does not apply.	spliceai cspec
PP4	Not met	Not found in the Li et al. 2020 (PMID:31853058) clinical history LR table for BRCA2. The variant was assessed in Parsons et al. 2019 multifactorial analysis (SuppT1 of HUMU-40-1557-s001): combined LR = 1.11 (co-occurrence LR = 1.02; family history LR = 1.08). The combined LR of 1.11 falls within the neutral zone (>0.48, <2.08) and does not reach the ENIGMA PP4_Supporting threshold of LR >= 2.08.	vcep_pmid_31853058_brca2_clinical_history_lr vcep_humu_40_1557_s001 cspec
PP5	N/A	ENIGMA BRCA2 VCEP specification states PP5 is Not Applicable for this VCEP, as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	ENIGMA BA1 requires FAF > 0.1% (0.001) in gnomAD non-founder populations. The gnomAD v4.1 grpmax FAF is 2.8e-07 (0.000028%), well below the BA1 stand-alone benign threshold. The variant is extremely rare in population databases.	gnomad_v4 cspec
BS1	Not met	ENIGMA BS1_Strong requires FAF > 0.01% (0.0001); BS1_Supporting requires FAF > 0.002% (0.00002) and <= 0.01%. The gnomAD v4.1 grpmax FAF is 2.8e-07 (0.000028%), which does not exceed either threshold. The variant is too rare to meet BS1 at any strength.	gnomad_v4 cspec
BS2	Not assessed	ENIGMA BS2 requires assessment of absence of Fanconi Anemia phenotype features in probands with co-occurrent variants in BRCA2. No proband-level phenotype data or co-occurrence data are available for this variant. Cannot assign BS2 without individual-level data.	cspec
BS3	Not met	Not listed in ENIGMA Specifications Table 9 (curated functional assay results for BRCA2). No published functional studies demonstrating a benign effect on protein function or splicing for this intronic variant.	vcep_specifications_table9_v1_2_2024_11_18 cspec
BS4	Not assessed	ENIGMA BS4 requires quantitative lack of segregation in affected family members (LR <= 0.48 for Supporting). No segregation data are available. The Parsons et al. 2019 SuppT1 combined LR of 1.11 is in the neutral zone, not meeting BS4 thresholds.	cspec vcep_humu_40_1557_s001
BP1	N/A	ENIGMA BP1 applies to silent substitutions, missense variants, or in-frame indels outside clinically important functional domains. This is an intronic substitution at c.7977-15; it is not a silent, missense, or in-frame coding variant. BP1 is not applicable to intronic variants.	cspec
BP2	N/A	ENIGMA BRCA2 VCEP specification marks BP2 as Not Applicable.	cspec
BP4	Met	Intronic variant at c.7977-15, outside the native acceptor splice site +/-1,2 positions. SpliceAI max delta score = 0.03 (<= 0.1), predicting no significant splicing impact. Meets ENIGMA BP4_Supporting criteria for intronic variants outside canonical splice sites with no predicted splicing effect.	spliceai cspec
BP5	Not met	Not found in the Li et al. 2020 (PMID:31853058) clinical history LR table for BRCA2. The Parsons et al. 2019 combined LR of 1.11 falls in the neutral zone (>0.48, <2.08) and does not meet the ENIGMA BP5_Supporting threshold of LR <= 0.48.	vcep_pmid_31853058_brca2_clinical_history_lr vcep_humu_40_1557_s001 cspec
BP6	N/A	ENIGMA BRCA2 VCEP specification marks BP6 as Not Applicable.	cspec
BP7	Not met	ENIGMA BP7_Supporting for intronic variants requires position at or beyond +7 (donor) or -21 (acceptor) AND BP4 met. This variant is at c.7977-15, which is 15 bases upstream of exon 18, within the -21 boundary of the acceptor splice site. Does not satisfy the positional requirement. BP7_Strong (RNA) requires mRNA assay data showing no damaging effect; no RNA assay data are available.	cspec spliceai
BP3	N/A	ENIGMA VCEP specification states BP3 is captured by bioinformatic tool prediction and domain analysis; not independently applied.	cspec
PM3	N/A	Skipped per user directive.
PM4	N/A	Skipped per user directive. Additionally, ENIGMA VCEP marks PM4 as Not Applicable.	cspec

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