LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Variant classification summary
BRCA2
· NP_000050.3:p.(Asn1747Ter)
· NM_000059.4
GRCh37: chr13:32913729 C>CT
·
GRCh38: chr13:32339592 C>CT
Gene:
BRCA2
Transcript:
NM_000059.4
Final call
Variant details
Gene
BRCA2
Transcript
NM_000059.4
Protein
NP_000050.3:p.(Asn1747Ter)
gnomAD AF
1.8624031705551575e-06 (v4.1)
ClinVar
Pathogenic
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
BRCA2 NM_000059.4:c.5238dupT (p.Asn1747Ter) is a frameshift variant in exon 11 resulting in a premature termination codon at position 1747. Loss of function is an established disease mechanism for BRCA2.
2
Per ENIGMA BRCA2 Specifications Table 4 (v1.2, 2024-11-18), PTC variants in exon 11 are assigned PVS1 at very strong strength. NMD is predicted as the PTC occurs well upstream of the final exon.
3
Per ENIGMA BRCA2 Specifications Table 4, exon 11 PTC variants also qualify for PM5_Strong (PTC), as exon 11 is not among the PM5_N/A exons (E6, E12, E27). Multiple proven pathogenic PTC variants have been observed in this exon.
4
In ClinVar (Variation ID 37954), this variant is classified as Pathogenic with review status 'reviewed by expert panel' (ENIGMA), supported by 39 clinical laboratory submissions. PP5 is applied at supporting strength per the ClinVar 3-star expert panel override.
5
The variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (AF=1.86e-06, 3/1,610,822 alleles, grpmax FAF=6.8e-07). Clinical-history likelihood ratio is neutral (LR=1.717).
6
Classification: Pathogenic. PVS1 (Very Strong) + PM5_Strong (PTC) satisfies ENIGMA Table 3 pathogenic combination rules (1 Very Strong + 1 Strong = Pathogenic).
Final determination:
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 | Met | BRCA2 c.5238dupT is a frameshift variant in exon 11 resulting in a premature termination codon at p.Asn1747Ter. Loss of function is an established disease mechanism for BRCA2. Per ENIGMA BRCA2 Specifications Table 4, PTC variants in exon 11 are assigned PVS1 at very strong strength. NMD is predicted as the PTC is located well upstream of the last exon (exon 27). The variant is absent from gnomAD v2.1. |
vcep_specifications_table4_v1_2_2024_11_18
pvs1_gene_context
gnomad_v2
|
| PM5 | Met | Per ENIGMA BRCA2 Specifications Table 4, PTC variants in exon 11 qualify for PM5_Strong (PTC). Exon 11 is not a PM5_N/A exon (PM5_N/A exons for BRCA2: E6, E12, E27 only). A PTC in exon 11 where other proven pathogenic PTC variants have been observed supports this additional weight. |
vcep_specifications_table4_v1_2_2024_11_18
|
| PP5 | Met | Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Pathogenic. |
clinvar
|
| PS1 | N/A | PS1 applies to missense substitutions or exonic/intronic variants with same predicted splicing impact as a previously classified pathogenic variant. This is a frameshift/duplication variant, not a missense substitution. |
|
| PS2 | N/A | PS2 is designated Not Applicable by the ENIGMA BRCA1/BRCA2 VCEP specification v1.2. |
cspec
|
| PS3 | N/A | ENIGMA Table 9 (PS3/BS3 functional assays) does not list this variant. Table 9 is calibrated for missense, synonymous, and selected splice-site variants. The variant is a frameshift/PTC; functional assay calibration is not applicable for null/frameshift variants in the ENIGMA framework as the PVS1+PM5 combination already captures the null effect. |
vcep_specifications_table9_v1_2_2024_11_18
|
| PS4 | Not met | No case-control study with p≤0.05 and OR≥4 is available for this variant. The variant has been observed in affected individuals (PMID:25682074 reports c.5237dup p.Asn1747* in a TNBC cohort), but no formal case-control statistical comparison has been performed per ENIGMA PS4 requirements. |
PMID:25682074
|
| PS5 | N/A | PS5 is not part of the ENIGMA BRCA1/BRCA2 VCEP framework. This criterion is not assessed under the active specification. |
|
| PM1 | N/A | PM1 is designated Not Applicable by the ENIGMA BRCA1/BRCA2 VCEP specification v1.2. |
cspec
|
| PM2 | Not met | The ENIGMA BRCA2 PM2 rule requires absence from gnomAD v2.1 (non-cancer, exome) AND v3.1 (non-cancer). The variant is absent from v2.1 but is present in gnomAD v4.1 at extremely low frequency (AF=1.86e-06; 3/1,610,822 alleles; highest in European non-Finnish, 3/1,177,880). Under strict CSPEC rules requiring absence from both v2.1 and v3.1, the presence in the successor v4.1 dataset precludes PM2_Supporting. |
gnomad_v2
gnomad_v4
|
| PM3 | N/A | PM3 is skipped per user directive — trivially not applicable for this case. |
|
| PM4 | N/A | PM4 is designated Not Applicable by the ENIGMA BRCA1/BRCA2 VCEP specification v1.2. |
cspec
|
| PM6 | N/A | PM6 is designated Not Applicable by the ENIGMA BRCA1/BRCA2 VCEP specification v1.2. |
cspec
|
| PP1 | Not met | No co-segregation data or quantitative segregation likelihood ratio is available for this variant. Per ENIGMA PP1 rules, a Bayes Score LR≥2.08 is required for Supporting strength. No such data has been provided. |
|
| PP2 | N/A | PP2 is designated Not Applicable by the ENIGMA BRCA1/BRCA2 VCEP specification v1.2. |
cspec
|
| PP3 | N/A | ENIGMA PP3 applies to missense/in-frame variants inside a functional domain with BayesDel≥0.30, or variants with SpliceAI≥0.2. This is a frameshift/PTC variant. BayesDel and REVEL are not applicable (not an SNV). SpliceAI max delta score is 0.00, indicating no predicted splicing impact. |
spliceai
|
| PP4 | Not met | Per PMID:31853058 clinical-history likelihood ratio table, BRCA2 c.5238dupT has LR=1.717 (LOG(LR)=0.540, N_Probands=10). This falls within the neutral zone (>0.48 and <2.08). Neither PP4 nor BP5 is applicable. |
vcep_pmid_31853058_brca2_clinical_history_lr
|
| BA1 | Not met | BA1 requires FAF > 0.1% (FAF > 0.001) in gnomAD v2.1/v3.1 non-cancer. The variant is absent from v2.1 and has grpmax FAF = 6.8e-07 (0.000068%) in v4.1, far below the BA1 threshold. |
gnomad_v2
gnomad_v4
|
| BS1 | Not met | BS1 requires FAF > 0.01% (Strong) or >0.002% (Supporting). The variant has grpmax FAF = 6.8e-07 (0.000068%), which is far below the BS1_Supporting threshold of 0.002%. Absent from gnomAD v2.1. BS1 is not met. |
gnomad_v2
gnomad_v4
|
| BS2 | Not met | BS2 requires documented absence of Fanconi Anemia phenotype features with sufficient proband points per ENIGMA Table 8. No proband-level phenotype data is available in the case materials to assess BS2. |
|
| BS3 | N/A | ENIGMA Table 9 (BS3 functional assays) does not list this variant. BS3 in the ENIGMA framework applies to missense/synonymous variants with calibrated functional studies showing no damaging effect. The variant is a frameshift/PTC, and its null effect is already captured by PVS1+PM5. |
vcep_specifications_table9_v1_2_2024_11_18
|
| BS4 | Not met | BS4 requires lack of segregation in affected family members, quantified by LR≤0.05 (Strong) or LR≤0.48 (Supporting). No segregation data is available for this variant. |
|
| BP1 | N/A | ENIGMA BP1 applies to silent substitutions, missense, or in-frame insertion/deletion variants outside a clinically important functional domain with no splicing predicted. This is a frameshift/PTC variant; BP1 does not apply. |
cspec
|
| BP2 | N/A | BP2 is designated Not Applicable by the ENIGMA BRCA1/BRCA2 VCEP specification v1.2. |
cspec
|
| BP3 | N/A | BP3 is designated Not Applicable by the ENIGMA BRCA1/BRCA2 VCEP specification v1.2. |
cspec
|
| BP4 | N/A | ENIGMA BP4 applies to missense/in-frame variants inside a functional domain with no predicted protein or splicing impact, or silent/intronic variants with no splicing impact. This is a frameshift/PTC variant; BP4 rules do not apply. |
|
| BP5 | Not met | Per PMID:31853058 clinical-history LR table, BRCA2 c.5238dupT has LR=1.717 which falls in the neutral zone (>0.48 and <2.08). Neither PP4 nor BP5 applies. |
vcep_pmid_31853058_brca2_clinical_history_lr
|
| BP6 | N/A | BP6 is designated Not Applicable by the ENIGMA BRCA1/BRCA2 VCEP specification v1.2. ClinVar classification is Pathogenic (expert panel reviewed), so the PP5/BP6 override would apply PP5 at supporting rather than BP6. |
cspec
|
| BP7 | N/A | ENIGMA BP7 applies to silent variants inside a clinically important functional domain, or intronic variants outside conserved splice motifs, when BP4 is met. This is a frameshift/PTC variant; BP7 rules do not apply. |
|
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.