The BRCA2 NM_000059.4:c.9097dup (NP_000050.3:p.(Thr3033AsnfsTer11)) frameshift variant has previously been reported in somatic cancers (COSMIC; COSV66447774, n = 25 times). This variant is predicted to result in an absent or disrupted protein product. Based on available guidelines, this variant is considered to be Pathogenic. This variant is considered to be Pathogenic by the VCEP (Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA); ClinVar ID 38208).
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
This variantScenario
BenignPathogenic
Pathogenic.A pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
About BRCA2
BRCA2 encodes a DNA repair protein that maintains genome stability by repairing double-strand breaks through homologous recombination and by protecting DNA replication forks. It acts as a tumor suppressor, and inherited loss-of-function changes cause hereditary breast and ovarian cancer syndrome, with elevated lifetime risks of breast, ovarian, prostate, and pancreatic cancers; biallelic changes cause Fanconi anemia complementation group D1. Reduced or altered BRCA2 activity is implicated in multiple tumor types, and PARP inhibitors are an approved treatment for BRCA2-associated ovarian and breast cancers.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is ClinGen BRCA2 VCEP v1.2. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Met at very strong: BRCA2 E23 Table 4 assigns PVS1, and c.9097 is upstream of the VCEP c.9600 NMD-escape threshold.
PM3Moderate
PM3 · moderate
Met at Moderate: one FA-D1 patient had compound-heterozygous BRCA2 variants, a phenotype-consistent presentation, and the VCEP assigns 2 PM3 points.
PM5Strong
PM5 · strong
Met at Strong: ENIGMA Table 4 assigns PM5_Strong (PTC) to BRCA2 exon 23, which contains c.9097 and is not PM5_N/A.
PP4Supporting
PP4 · supporting
Met at Supporting: the exact-variant clinical-history LR is 2.955961503957612, satisfying the ENIGMA PP4 threshold 2.955961503957612 ≥ 2.08.
PP5Supporting
PP5 · supporting
Not applicable: the ENIGMA BRCA2 specification explicitly marks PP5 Not Applicable.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Pathogenic
Pathogenic: PVS1 (very strong) plus PM3 (moderate) satisfy the ENIGMA BRCA2 VCEP Table 3 Pathogenic rule, with additional PM5, PP4, and PP5 evidence.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
10 / 1,612,818 alleles
gnomAD v4.1: 10 / 1,612,818 alleles. Recorded AF 6.20033e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.21975e-05; MAF= 0.00122%, 3/245952 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.28615e-05; MAF= 0.00629%, 1/15908 alleles, homozygotes = 0); grpmax FAF= 3.01e-06.
ACMG/AMP criteria under ClinGen BRCA2 VCEP v1.2, with the data and sources behind each one.
28 criteria with recorded statuses: 5 met · 2 not met · 8 not assessed · 13 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
PVS1 is met at very strong strength because the exact BRCA2 frameshift is assigned PVS1 in the governing E23 Table 4 row and lies upstream of the VCEP c.9600 NMD-escape threshold.
PM4 and BP3 are not applicable because the ENIGMA BRCA2 specification explicitly says not to use either criterion for this framework.
The ENIGMA clinical-history table provides LR=2.955961503957612 for the exact c.9097dupA row, supporting PP4 and failing the opposite-direction BP5 threshold.
The available exact-variant literature reports affected individuals but does not provide the case-control data required by PS4.
PP5 and BP6 are explicitly Not Applicable in the governing ENIGMA BRCA2 CSPEC entries.
Governing framework: ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications for BRCA2 v1.2.
NM_000059.4:c.9097dup is normalized as NP_000050.3:p.(Thr3033AsnfsTer11) / p.(T3033Nfs*11), a frameshift variant.
PP3, BP4, and BP7 are each upstream not_applicable because the VCEP-defined computational pathways do not include frameshift variants.
The matching SupplementaryTables row is a Class 5 truncating-variant annotation and does not pre-assign any of PP3, BP4, or BP7.
SpliceAI max delta 0.208 was not used because splice prediction cannot make these criteria applicable to a frameshift variant.
No criteria match.
Met · 5
PVS1Very strongVCEPMet at very strong: BRCA2 E23 Table 4 assigns PVS1, and c.9097 is upstream of the VCEP c.9600 NMD-escape threshold.
Details ▾Hide ▴
Reasoning
NM_000059.4:c.9097dup is a one-base coding duplication producing the frameshift NP_000050.3:p.(Thr3033AsnfsTer11), a null consequence in BRCA2. The governing ENIGMA Table 4 row for BRCA2 E23 assigns PVS1 to PTC variants; the row covers exon 23 coding sequence c.8954-c.9117 and protein positions p.2985-p.3039. The variant at c.9097 is upstream of the Appendix D statement that PTC from c.9600 onwards is not predicted to result in NMD, so no named NMD-escape downgrade applies. The exact variant is independently reported as c.9097dupA causing frameshift and premature protein truncation.
VCEP rule
Null variant in a gene where loss of function is a known mechanism of disease. ... Apply according to PVS1 flowchart, which considers knowledge of clinically important functional domains. For predicted protein termination codon (PTC) variants, apply with exon-specific weights derived for the PM5 (PTC) code (see description below). ... See Table 4, provided as a separate searchable excel file, for a comprehensive summary of codes applicable for all variants considered against the BRCA1 and BRCA2 PVS1 decision trees (initiation, nonsense/frameshift, deletion, duplication, splice site (donor/acceptor ±1,2)) – organized by exon. ... PTC from position c.9600 onwards are not predicted to result in NMD.
Evidence considered
ENIGMA Specifications v1.2, Table 4, BRCA2 E23 row: coding PTC variants are assigned PVS1; the row lists exon 23 c.8954-c.9117 and p.2985-p.3039.
ENIGMA Specifications v1.2, Appendix D, BRCA2 PVS1 decision-tree note: PTC from position c.9600 onwards are not predicted to result in NMD; c.9097 is upstream of that position.
ENIGMA Supplementary Tables v1.2, matching row BRCA2 c.9097dupA / p.(Thr3033Asnfs*11): variant allele predicted to encode a truncated non-functional protein.
Kopic et al. 2011, PMID:21138478, exact-variant case-report passage: c.9097dupA is a 1-bp duplication leading to frameshift and premature protein truncation, p.T3033NfsX10, equivalent to normalized p.(Thr3033AsnfsTer11).
Wong-Brown et al. 2015, PMID:25682074, Table 2 row: BRCA2 exon 23 c.9097dup / p.Thr3033Asnfs*11, BIC class 5 pathogenic.
PM3ModerateVCEPMet at Moderate: one FA-D1 patient had compound-heterozygous BRCA2 variants, a phenotype-consistent presentation, and the VCEP assigns 2 PM3 points.
Details ▾Hide ▴
Reasoning
PM3 is met at Moderate strength (2 points). The exact variant, reported as c.9097dupA/p.(Thr3033Asnfs*11), was observed in a girl with BRCA2-related Fanconi anaemia (FA-D1) as one of two biallelic, compound-heterozygous BRCA2 variants; the other allele was c.7878G>C/p.(Trp2626Cys). The report describes increased chromosome-breakage-related FA cellular abnormalities, including mitomycin-C hypersensitivity, G2-phase accumulation, and failure to form RAD51 foci, plus hepatoblastoma at 4 years and 3 months. The ENIGMA supplementary table gives the co-occurrent c.7878G>C allele Class 5 and the c.9097dupA row as Class 5, and identifies the Kopic 2011 case (PMID:21138478). This satisfies the VCEP Table 6 row for a phenotype-consistent FA patient with a pathogenic/likely pathogenic variant in trans or a homozygous configuration, yielding 2 PM3 points; the observed compound-heterozygous configuration supports the in-trans interpretation.
VCEP rule
Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene. ... Phenotype is considered consistent with BRCA1- or BRCA2-related FA if: ... (i) Increased chromosome breakage (DEB, MMC, or spontaneous) and at least one clinical feature indicative of BRCA1/2-related FA, categorized under: physical features, pathology and laboratory findings, cancer diagnosis ≤5yr. ... See Table 6 for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. ... Assign final PM3 code based on sum of PM3-related points from observations across multiple unrelated individuals, as follows: ... PM3_Strong = 4 (or more) points; PM3 = 2 points; PM3_Supporting = 1 point.
Evidence considered
Kopic et al. 2011, PMID:21138478, case report: c.9097dupA/p.T3033NfsX10 (equivalent to p.(T3033Nfs*11)) occurred with c.7878G>C/p.W2626C as biallelic compound-heterozygous BRCA2 mutations in a girl with FA-D1; the patient had Fanconi-anaemia-associated cellular abnormalities and hepatoblastoma at 4 years and 3 months.
ENIGMA SupplementaryTables_V1.2_2024-11-18.xlsx, row beginning c.9097dupA p.(Thr3033Asnfs*11): co-occurrent c.7878G>C p.(Trp2626Cys), no phase uncertainty indicated, Class 5 for the co-occurrent variant, and PMID:21138478 for the Kopic 2011 case.
ENIGMA Specifications Table 6: the row for a BRCA1/2-related FA patient with a P or LP variant in trans or homozygote assigns 2 points; the table states PM3 = 2 points and PM3_Supporting = 1 point.
Still missing
Specifications_V1.2_2024-11-18.docx was searched for c.9097dup, p.Thr3033AsnfsTer11, and p.T3033Nfs*11; it contains the governing PM3 rule but no variant-specific row.
PM5StrongVCEPMet at Strong: ENIGMA Table 4 assigns PM5_Strong (PTC) to BRCA2 exon 23, which contains c.9097 and is not PM5_N/A.
Details ▾Hide ▴
Reasoning
The variant is a protein-termination frameshift in BRCA2 exon 23: c.9097 lies within the Table 4 exon-23 coding interval c.8954-c.9117, and the encoded consequence is p.(Thr3033AsnfsTer11). ENIGMA Table 4 preassigns PVS1 for the exon-23 PTC category and PM5_Strong (PTC); exon 23 is not among the BRCA2 PM5_N/A exons. Therefore the VCEP-governed PM5_PTC code is met at Strong strength.
VCEP rule
Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1. See Specifications Table 4 for PM5_PTC code strengths applicable per exon. See Appendix D for additional details.
Evidence considered
Specifications Table 4, BRCA2 E23 row: the exon spans c.8954-c.9117 and assigns PVS1 to the PTC category and PM5_Strong (PTC); the same table lists PM5_N/A only for BRCA2 E6, E12, and E27.
The case consequence is NP_000050.3:p.(Thr3033AsnfsTer11), a protein-terminating frameshift at c.9097.
Supplementary Tables ST9 row c.9097dupA / p.(Thr3033Asnfs*11) records a truncated non-functional protein prediction and Class 5 context.
PP4SupportingVCEPMet at Supporting: the exact-variant clinical-history LR is 2.955961503957612, satisfying the ENIGMA PP4 threshold 2.955961503957612 ≥ 2.08.
Details ▾Hide ▴
Reasoning
Li et al. 2020 Supplementary Table 4 reports the exact BRCA2 row c.9097dupA with LOG(LR)=0.4706987738609314 and LR=2.955961503957612. The ENIGMA PP4 Supporting rule uses combined multifactorial clinical LR and requires LR ≥2.08:1; the explicit comparison is 2.955961503957612 ≥ 2.08? yes. Therefore PP4 Supporting is met.
VCEP rule
Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data. ... PP4 - LR ≥2.08:1 ... See Specifications Table7 and Appendix B for details.
Evidence considered
Li et al. 2020, BRCA2 clinical-history LR table, Supplementary Table 4, row BRCA2 c.9097dupA: LOG(LR)=0.4706987738609314, N=10, LR=2.955961503957612.
ENIGMA PP4 Supporting operator quoted from the VCEP rule is LR ≥2.08:1; substituted inequality: 2.955961503957612 ≥ 2.08? yes.
The table is used only as the ENIGMA multifactorial clinical-history LR component, as specified by the governing VCEP material.
BS2VCEPNot met: the exact variant was observed in a child with Fanconi anaemia features and hepatoblastoma at 4 years, not an unaffected adult presentation.
Details ▾Hide ▴
Reasoning
BS2 is applied only when the required unaffected or presumed FA-unaffected presentation supports the point-based rule. The exact variant was reported as c.9097dupA in trans with c.7878G>C in a child with Fanconi anaemia group D1, congenital anomalies, chromosome-breakage abnormalities, and hepatoblastoma diagnosed at 4 years and 3 months. This is the opposite of the absence of Fanconi Anaemia features required by the VCEP rule, and no qualifying healthy-adult BS2 observation is available.
VCEP rule
Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See Table 8 for approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points.
Evidence considered
ENIGMA BRCA2 specification v1.2: BS2 is applied in the absence of features of recessive disease, namely Fanconi Anaemia phenotype, with final strength based on the Table 8 point total.
Kopic et al. 2011, PMID:21138478, exact variant report: c.9097dupA caused p.T3033NfsX10 and occurred biallelically with c.7878G>C in a child with Fanconi anaemia group D1; the child had congenital malformations, elevated chromosome breakage, cellular hypersensitivity to mitomycin C, and hepatoblastoma at 4 years and 3 months.
Still missing
No qualifying unaffected-adult or presumed FA-unaffected BS2 observation with the required point assignment was identified.
HUMU-40-1557-s001.xlsx was searched for c.9097dupA, c.9097dup, p.(T3033Nfs*11), and p.T3033Nfs*11; no exact entry was found.
BP5VCEPNot met: the exact-variant LR is 2.955961503957612, which fails the ENIGMA BP5 Supporting inequality 2.955961503957612 ≤ 0.48.
Details ▾Hide ▴
Reasoning
Li et al. 2020 Supplementary Table 4 reports the exact BRCA2 row c.9097dupA with LR=2.955961503957612. The ENIGMA BP5 Supporting rule requires LR ≤0.48:1, and the explicit comparison is 2.955961503957612 ≤ 0.48? no. The LR is therefore outside the BP5 benign-supporting range; no BP5 strength is assigned.
VCEP rule
Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data. ... BP5 - LR ≤0.48:1 ... Not applicable for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype.
Evidence considered
Li et al. 2020, BRCA2 clinical-history LR table, Supplementary Table 4, row BRCA2 c.9097dupA: LOG(LR)=0.4706987738609314, N=10, LR=2.955961503957612.
ENIGMA BP5 Supporting operator quoted from the VCEP rule is LR ≤0.48:1; substituted inequality: 2.955961503957612 ≤ 0.48? no.
PS1VCEPNot assessed: the frameshift has SpliceAI max delta 0.208, but no qualifying pathogenic comparator with the same precisely predicted splicing event is available.
Details ▾Hide ▴
Reasoning
The variant is a frameshift, not a predicted missense substitution. The ENIGMA specification also permits PS1 for an exonic variant with the same predicted splicing impact as a previously classified pathogenic or likely pathogenic variant, but the available evidence provides no qualifying comparator with a precisely matching predicted splicing event. SpliceAI max delta is 0.208, above the specification's no-splicing threshold of 0.1, so the missense PS1 path cannot be used and the splice PS1 path cannot be resolved.
VCEP rule
Apply PS1, for predicted missense substitutions, where a previously classified pathogenic variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)). ... Apply PS1_Variable Weight, for exonic and intronic variants with same predicted impact on splicing, as a previously classified (likely) pathogenic variant. Vary weight depending on relative positions, and confidence in classification of the reference variant.
Evidence considered
Case normalization identifies NM_000059.4:c.9097dup as NP_000050.3:p.(Thr3033AsnfsTer11), a frameshift rather than a missense substitution.
The case SpliceAI result is max delta 0.208 (DS_AL 0.208).
Searches of the governing BRCA2 full-text files for c.9097dup, p.Thr3033AsnfsTer11, and p.T3033Nfs*11 found the exact variant in SupplementaryTables_V1.2_2024-11-18.xlsx.txt, but no PS1 comparator entry in Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
Still missing
No qualifying previously classified pathogenic or likely pathogenic comparator with a precisely matching predicted splicing event was identified in the available evidence.
PS3VCEPNot assessed: the exact variant lacks a calibrated Table 9 assay, and the available compound-heterozygous fibroblast study does not isolate BRCA2 protein-function impact.
Details ▾Hide ▴
Reasoning
The ENIGMA BRCA2 rule requires well-established functional studies demonstrating a damaging effect and directs use of calibrated published assays in Specifications Table 9. The exact variant is absent from Table 9, and no pre-assigned PS3 code was found in the governing VCEP files. PMID:21138478 reports the exact c.9097dupA/p.T3033NfsX10 allele in a compound-heterozygous Fanconi anaemia case, but its fibroblast results (mitomycin-C hypersensitivity, G2 accumulation, and absent RAD51 foci) are cellular disease-phenotype observations in a patient carrying a second BRCA2 variant, not a calibrated assay of isolated BRCA2 protein function. The VCEP's same-exon PTC inference statement therefore does not supply a directly applicable pre-assigned code for this variant. PS3 cannot be evaluated from the available qualifying evidence.
VCEP rule
Well-established in vitro or in vivo functional studies supportive of a damaging effect. Apply PS3 for assays measuring effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.
Evidence considered
Specifications Table 9: the file states that additional published assay results not listed there must be reviewed under Figure 1C, but no row matches c.9097dup/c.9097dupA or p.Thr3033AsnfsTer11/p.T3033Nfs*11.
Appendix E, 'Justification for PM5 (PTC) exon-specific weights': 'The observation of impact on function for at least one PTC variant in an exon, where this variant is not predicted (or shown) to alter splicing with potential to rescue function, can be used to infer code PS3 for another PTC variant in the same exon.'
The case's SpliceAI result is max delta score 0.208, so a no-predicted-splicing condition cannot be presumed for this variant.
Kopic et al. 2011, PMID:21138478, reports the exact allele as c.9097dupA/p.T3033NfsX10 in a compound-heterozygous FA-D1 case; fibroblasts showed mitomycin-C hypersensitivity, G2-phase accumulation, and failure to form RAD51 foci, but the study does not provide an isolated, calibrated BRCA2 protein-function assay for this allele.
Still missing
No exact c.9097dup, c.9097dupA, p.Thr3033AsnfsTer11, or p.T3033Nfs*11 entry was found in Specifications_Table9_V1.2_2024-11-18.xlsx.txt.
No exact variant entry was found in Specifications_V1.2_2024-11-18.docx.txt.
No exact variant entry was found in Appendices_V1.2_2024-11-18.docx.txt.
No exact variant entry was found in HUMU-40-1557-s001.xlsx.txt.
A direct calibrated protein-function assay for this exact frameshift, or an ENIGMA-validated same-exon inference path satisfying the splicing conditions, remains unavailable.
PS4VCEPNot assessed: one affected TNBC carrier was reported, but no control count or case-control statistics were available for the required PS4 comparison.
Details ▾Hide ▴
Reasoning
The exact variant is reported in one affected individual in a Polish triple-negative breast cancer cohort of 335 patients (PMID:25682074), but the paper provides no unaffected or population-control count for this variant. The ENIGMA PS4 rule requires a case-control study with p-value ≤0.05, OR ≥4, and a lower confidence interval excluding 2.0; these cannot be calculated from the available variant-level report. The literature_pass.json packet has an empty ai_classified_papers list, so there were no pre-classified PS4 papers requiring additional verification. The ENIGMA supplementary tables were searched under c.9097dup, c.9097dupA, p.Thr3033AsnfsTer11, and p.T3033Nfs*11; the ST9 row records the exact variant in a Fanconi-anemia case, not a PS4 case-control comparison.
VCEP rule
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Case-control studies; p-value ≤0.05 and OR ≥4 (lower confidence interval excludes 2.0).
Evidence considered
ClinGen ENIGMA BRCA2 specification PS4 rule: case-control studies require p-value ≤0.05, OR ≥4, with the lower confidence interval excluding 2.0.
SupplementaryTables_V1.2_2024-11-18.xlsx, ST9 BRCA2 FA row: c.9097dupA, p.(Thr3033Asnfs*11), Class 5, Kopic 2011, PMID:21138478; this is a Fanconi-anemia case record and does not provide PS4 case-control counts.
PMID:25682074, Table 2, Polish cohort, BRCA2 exon 23: c.9097dup, p.Thr3033Asnfs*11, one carrier (patient 285,224) among 335 Polish triple-negative breast cancer patients; no control carrier count is reported.
The required variant notations were searched in the governing ENIGMA full-text files; no PS4 case-control row was found for c.9097dup or its listed protein notations.
Still missing
PMID:25682074 reports one carrier among 335 Polish triple-negative breast cancer patients but does not report unaffected or population controls carrying c.9097dup.
No usable case-control p-value, odds ratio, or 95% confidence interval was found for c.9097dup in SupplementaryTables_V1.2_2024-11-18.xlsx.
No usable case-control p-value, odds ratio, or 95% confidence interval was found for c.9097dup in HUMU-40-1557-s001.xlsx.
literature_pass.json ai_classified_papers was empty; no pre-classified PS4 paper was available for verification.
PP1VCEPNot assessed: no variant-specific family segregation data or quantitative LR is available, so the PP1 threshold of LR ≥2.08:1 cannot be evaluated.
Details ▾Hide ▴
Reasoning
PP1 requires co-segregation in multiple affected family members measured by a quantitative co-segregation method and a Bayes-score LR of at least 2.08:1 for supporting strength. The case materials provide no variant-specific pedigree, affected-relative count, meioses, parental testing, or quantitative segregation LR. HUMU-40-1557-s001.xlsx.txt was searched for c.9097dup, c.9097dupA, p.Thr3033AsnfsTer11, and p.T3033Nfs*11 with no entry. SupplementaryTables_V1.2_2024-11-18.xlsx.txt contains a c.9097dupA / p.(Thr3033Asnfs*11) row classified Class 5, but it provides no PP1 segregation LR and was not used for PP1.
VCEP rule
Co-segregation with disease in multiple affected family members ... Apply weight as per Bayes Score: ... PP1 - LR ≥2.08:1 ... PP1_Moderate – LR≥4.3:1 ... PP1_Strong – LR≥18.7:1 ... PP1_Very Strong – LR≥350:1
Evidence considered
Specifications V1.2, PP1_VariableWeight: co-segregation with disease in multiple affected family members; supporting PP1 requires LR ≥2.08:1, moderate requires LR ≥4.3:1, strong requires LR ≥18.7:1, and very strong requires LR ≥350:1.
HUMU-40-1557-s001.xlsx.txt: no matching entry was found for c.9097dup, c.9097dupA, p.Thr3033AsnfsTer11, or p.T3033Nfs*11; therefore this file supplies no variant-specific segregation LR for PP1.
SupplementaryTables_V1.2_2024-11-18.xlsx.txt, matched row: c.9097dupA; p.(Thr3033Asnfs*11); Class 5; the row contains no quantitative co-segregation LR and was not used to assign PP1.
Still missing
No variant-specific pedigree or affected-relative segregation data were available.
No quantitative co-segregation Bayes-score LR or meioses count was available.
HUMU-40-1557-s001.xlsx.txt was searched for c.9097dup, c.9097dupA, p.Thr3033AsnfsTer11, and p.T3033Nfs*11; no entry was found.
SupplementaryTables_V1.2_2024-11-18.xlsx.txt was searched and contains c.9097dupA / p.(Thr3033Asnfs*11), but that row supplies a Class 5 classification and no PP1 segregation LR.
BA1VCEPNot assessed: required non-cancer gnomAD FAF is unavailable; available all-comers grpmax FAFs are 3.01e-06 and 2.92e-06, below 0.001.
Details ▾Hide ▴
Reasoning
The ENIGMA rule requires the maximum filter allele frequency from the specified non-cancer, non-founder gnomAD populations, with a threshold above 0.001. The available evidence contains only all-comers gnomAD totals and subpopulation frequencies: gnomAD v2.1 total AF 1.21975e-05 with grpmax FAF 3.01e-06, and gnomAD v4.1 total AF 6.20033e-06 with grpmax FAF 2.92e-06; these cannot substitute for the required gnomAD v2.1 non-cancer exome or v3.1 non-cancer genome values. Read depth and quality-control status are also not available. Therefore BA1 cannot be assessed.
VCEP rule
Filter allele frequency (FAF) is above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.
Evidence considered
ENIGMA BRCA2 specification v1.2: BA1 requires FAF above 0.001 in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes, using the maximum filter allele frequency in a non-founder population and excluding records with read depth below 20 or failed quality control.
gnomAD v2.1 all-comers record: total AF 1.21975e-05, 3/245952 alleles, zero homozygotes, highest observed subpopulation AF 6.28615e-05 in African/African American individuals, grpmax FAF 3.01e-06; this is not the required non-cancer subset.
gnomAD v4.1 all-comers record: total AF 6.20033e-06, 10/1612818 alleles, zero homozygotes, highest observed subpopulation AF 3.38043e-05 in Ashkenazi Jewish individuals, grpmax FAF 2.92e-06; this is not the VCEP-specified v3.1 non-cancer genome source.
Still missing
GNOMAD_V2_1_NON_CANCER exome-only FAF and GNOMAD_V3_1_NON_CANCER genome FAF are not present in the case evidence.
Read depth and variant quality-control status for the governing population records are unavailable.
HUMU-40-1557-s001.xlsx was searched for c.9097dupA, c.9097dup, p.(T3033Nfs*11), and p.T3033Nfs*11; no exact entry was found.
BS1VCEPNot assessed: required non-cancer FAF is unavailable; available all-comers grpmax FAFs are 3.01e-06 and 2.92e-06, below the 0.00002 Supporting threshold.
Details ▾Hide ▴
Reasoning
The ENIGMA rule requires the maximum filter allele frequency from the specified non-cancer, non-founder gnomAD populations, with Supporting weight for FAF >0.00002 to <=0.0001 and Strong weight for FAF >0.0001. The available all-comers records show grpmax FAF 3.01e-06 in gnomAD v2.1 and 2.92e-06 in gnomAD v4.1, but the required non-cancer v2.1 exome and v3.1 genome records are unavailable. Because the governing source population is missing, BS1 cannot be assessed rather than evaluated from the all-comers values.
VCEP rule
Filter allele frequency (FAF) is above 0.01% (FAF > 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details. ... Filter allele frequency (FAF) is above 0.002% (FAF > 0.00002) and less than or equal to 0.01% (FAF ≤ 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.
Evidence considered
ENIGMA BRCA2 specification v1.2: BS1 is Strong for FAF >0.0001 and Supporting for FAF >0.00002 to <=0.0001 in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes, using the maximum non-founder filter allele frequency and excluding records with read depth below 20 or failed quality control.
gnomAD v2.1 all-comers record: grpmax FAF 3.01e-06, total AF 1.21975e-05, and zero homozygotes; this does not provide the required non-cancer subset.
gnomAD v4.1 all-comers record: grpmax FAF 2.92e-06, total AF 6.20033e-06, and zero homozygotes; this does not provide the VCEP-specified v3.1 non-cancer genome source.
Still missing
GNOMAD_V2_1_NON_CANCER exome-only FAF and GNOMAD_V3_1_NON_CANCER genome FAF are not present in the case evidence.
Read depth and variant quality-control status for the governing population records are unavailable.
HUMU-40-1557-s001.xlsx was searched for c.9097dupA, c.9097dup, p.(T3033Nfs*11), and p.T3033Nfs*11; no exact entry was found.
BS3VCEPNot assessed: no calibrated benign functional assay or pre-assigned BS3 code exists for the exact c.9097dup frameshift in the governing ENIGMA materials.
Details ▾Hide ▴
Reasoning
The ENIGMA BRCA2 rule requires well-established functional studies showing no damaging effect on protein function and directs use of calibrated published assays in Specifications Table 9. The exact variant is absent from Table 9 and no benign functional assay, neutral result, or pre-assigned BS3 code was found in the governing VCEP files. The available exact-variant publication reports a damaging Fanconi anaemia cellular phenotype in a compound-heterozygous patient, not a benign protein-function result. Therefore BS3 cannot be evaluated.
VCEP rule
Well-established in vitro or in vivo functional studies shows no damaging effect on protein function. Assay measures effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.
Evidence considered
Specifications Table 9: no row matches c.9097dup/c.9097dupA or p.Thr3033AsnfsTer11/p.T3033Nfs*11, and therefore no pre-assigned BS3 strength is available.
Kopic et al. 2011, PMID:21138478, reports a disruptive frameshift allele in a compound-heterozygous FA-D1 case with abnormal fibroblast assays; this is not benign or neutral functional evidence.
Still missing
No exact c.9097dup, c.9097dupA, p.Thr3033AsnfsTer11, or p.T3033Nfs*11 entry was found in Specifications_Table9_V1.2_2024-11-18.xlsx.txt.
No exact variant entry was found in Specifications_V1.2_2024-11-18.docx.txt.
No exact variant entry was found in Appendices_V1.2_2024-11-18.docx.txt.
No exact variant entry was found in HUMU-40-1557-s001.xlsx.txt.
A validated benign or neutral protein-function assay for this exact frameshift remains unavailable.
BS4VCEPNot assessed: no variant-specific non-segregation data or quantitative LR is available, so the BS4 threshold of LR ≤0.48:1 cannot be evaluated.
Details ▾Hide ▴
Reasoning
BS4 requires lack of segregation in affected family members measured by a quantitative co-segregation method and a Bayes-score LR of at most 0.48:1 for supporting strength, at most 0.23:1 for moderate strength, or at most 0.05:1 for strong strength. The case materials provide no variant-specific pedigree, affected-relative count, meioses, parental testing, non-segregation observations, or quantitative segregation LR. HUMU-40-1557-s001.xlsx.txt was searched for c.9097dup, c.9097dupA, p.Thr3033AsnfsTer11, and p.T3033Nfs*11 with no entry. SupplementaryTables_V1.2_2024-11-18.xlsx.txt contains a c.9097dupA / p.(Thr3033Asnfs*11) row classified Class 5, but it provides no BS4 segregation LR and was not used for BS4.
VCEP rule
Lack of segregation in affected members of a family. ... Apply weight as per Bayes Score: ... BS4_Supporting - LR ≤0.48 to >0.23:1 ... BS4_Moderate - LR ≤0.23:1 ... BS4 - LR ≤0.05:1 ... BS4_Very strong – LR ≤0.00285:1
Evidence considered
Specifications V1.2, BS4_VariableWeight: lack of segregation in affected family members; supporting BS4 requires LR ≤0.48 to >0.23:1, moderate requires LR ≤0.23:1, strong requires LR ≤0.05:1, and very strong requires LR ≤0.00285:1.
HUMU-40-1557-s001.xlsx.txt: no matching entry was found for c.9097dup, c.9097dupA, p.Thr3033AsnfsTer11, or p.T3033Nfs*11; therefore this file supplies no variant-specific non-segregation LR for BS4.
SupplementaryTables_V1.2_2024-11-18.xlsx.txt, matched row: c.9097dupA; p.(Thr3033Asnfs*11); Class 5; the row contains no quantitative co-segregation LR and was not used to assign BS4.
Still missing
No variant-specific pedigree or affected-relative non-segregation data were available.
No quantitative co-segregation Bayes-score LR or meioses count was available.
HUMU-40-1557-s001.xlsx.txt was searched for c.9097dup, c.9097dupA, p.Thr3033AsnfsTer11, and p.T3033Nfs*11; no entry was found.
SupplementaryTables_V1.2_2024-11-18.xlsx.txt was searched and contains c.9097dupA / p.(Thr3033Asnfs*11), but that row supplies a Class 5 classification and no BS4 segregation LR.
Not applicable · 13· recorded as not applicableShow reasons ▾Hide reasons ▴PS2VCEPNot applicable: the ENIGMA BRCA2 specification explicitly says not to use PS2 because de novo occurrences lack calibrated predictive value.
Details ▾Hide ▴
Reasoning
The ENIGMA BRCA2 specification explicitly says not to use PS2 because BRCA1/2-related cancers occur relatively commonly and there is no information to calibrate the predictive capacity of de novo occurrences. This criterion is therefore not applicable regardless of whether paternity or family-history information is available.
VCEP rule
De novo (paternity confirmed) in a patient with the disease and no family history. ... Do not use ... BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.
Evidence considered
Specifications V1.2, PS2 entry: the criterion is marked Do not use because BRCA1/2-related cancers occur relatively commonly and de novo occurrences are not calibrated for predictive capacity.
PM1VCEPNot applicable: ENIGMA explicitly says PM1 is not used for BRCA2 and evaluates domain information through BP1, BP4, and PP3 instead.
Details ▾Hide ▴
Reasoning
The ENIGMA BRCA2 specification explicitly marks PM1 as not for use and states that it is considered as part of the bioinformatic analysis instead. The authoritative vcep_materials.json domain_tables object is empty, so there is no additional approved domain list that changes this governing PM1 disposition.
VCEP rule
Located in a mutational hot spot and/or critical and well-established functional domain. ... Do not use ... Considered as component of bioinformatic analysis (PP3/BP4).
Evidence considered
Specifications V1.2, PM1 row: the criterion is marked Do not use and is considered a component of bioinformatic analysis (PP3/BP4).
Appendix J Table 16: PM1 is N/A and domain information is evaluated under BP1, BP4, and PP3.
The authoritative vcep_materials.json domain_tables object contains no BRCA2 entries.
PM2N/ANot applicable: ENIGMA explicitly excludes insertion, deletion, and delins variants from PM2, regardless of the observed gnomAD allele counts.
Details ▾Hide ▴
Reasoning
The variant is a 1-bp duplication/frameshift. ENIGMA BRCA2 v1.2 explicitly excludes insertion, deletion, and delins variants from PM2, so the population observations cannot support PM2 even though gnomAD reports the variant at 3/245952 alleles in v2.1 and 10/1612818 alleles in v4.1 with zero homozygotes. The VCEP's additional PM2 read-depth requirement is therefore not reached.
VCEP rule
Absent from controls in an outbred population, from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer). Region around the variant must have an average read depth ≥25. See Appendix G for details. ... Observation of a variant only once in a gnomAD outbred population is not informative (no code applied). Do not apply for insertion, deletion or delins variants.
Evidence considered
ENIGMA BRCA2 specification v1.2: PM2 Supporting requires absence from the specified controls, average read depth at least 25, and explicitly states not to apply for insertion, deletion or delins variants.
SupplementaryTables_V1.2_2024-11-18.xlsx exact variant row: c.9097dupA, p.(Thr3033Asnfs*11), classified as a truncation/Class 5; this is not a PM2 population assignment.
gnomAD v2.1 all-comers record: 3/245952 alleles, AF 1.21975e-05, zero homozygotes.
gnomAD v4.1 all-comers record: 10/1612818 alleles, AF 6.20033e-06, zero homozygotes.
Still missing
HUMU-40-1557-s001.xlsx was searched for c.9097dupA, c.9097dup, p.(T3033Nfs*11), and p.T3033Nfs*11; no exact entry was found.
PM4VCEPNot applicable: the VCEP says not to use PM4 and limits it to in-frame length changes or stop-loss variants.
Details ▾Hide ▴
Reasoning
The ENIGMA BRCA2 specification explicitly says not to use PM4 and defines it for in-frame deletions/insertions in a non-repeat region or stop-loss variants. This variant is a frameshift duplication, not one of the named PM4 variant types.
VCEP rule
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. ... Do not use ... Considered as component of bioinformatic analysis (PP3/BP4).
Evidence considered
ENIGMA Specifications v1.2, PM4 entry: protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants; the specification says Do not use and routes this to PP3/BP4 bioinformatic analysis.
ClinGen ENIGMA BRCA2 CSPEC PM4 entry: applicability is Not Applicable.
PM6VCEPNot applicable: the ENIGMA BRCA2 specification explicitly says not to use PM6 because de novo occurrences lack calibrated predictive value.
Details ▾Hide ▴
Reasoning
The ENIGMA BRCA2 specification explicitly says not to use PM6 because BRCA1/2-related cancers occur relatively commonly and there is no information to calibrate the predictive capacity of de novo occurrences. This criterion is therefore not applicable even without confirmed paternity and maternity.
VCEP rule
Confirmed de novo without confirmation of paternity and maternity. ... Do not use ... BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.
Evidence considered
Specifications V1.2, PM6 entry: the criterion is marked Do not use because BRCA1/2-related cancers occur relatively commonly and de novo occurrences are not calibrated for predictive capacity.
PP2VCEPNot applicable: ENIGMA says PP2 is not used because missense variants are not a common BRCA2 pathogenic mechanism.
Details ▾Hide ▴
Reasoning
The ENIGMA BRCA2 specification explicitly marks PP2 as not for use because missense variants are not a common mechanism of pathogenicity for BRCA1 and BRCA2. The case variant is also a frameshift rather than a missense variant.
VCEP rule
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. ... Do not use ... High frequency of benign missense variants.
Evidence considered
Specifications V1.2, PP2 row: Do not use; high frequency of benign missense variants.
Appendix J Table 16 states that missense variants are not a common mechanism of pathogenicity for BRCA1 and BRCA2.
PP3N/ANot applicable: ENIGMA limits PP3 to missense/in-frame, silent, or eligible intronic variants, whereas c.9097dup is a frameshift.
Details ▾Hide ▴
Reasoning
NM_000059.4:c.9097dup produces NP_000050.3:p.(Thr3033AsnfsTer11), a frameshift variant. The ENIGMA BRCA2 v1.2 PP3 rule defines a protein-impact pathway only for missense or in-frame insertion, deletion, or delins variants inside a clinically important functional domain, and a splice-prediction pathway only for silent, missense/in-frame, or eligible intronic variants. A frameshift is outside every PP3 variant-type pathway, so PP3 is not applicable before any predictor score is considered. The available SpliceAI maximum delta score of 0.208 is therefore not used to assign PP3. The SupplementaryTables V1.2 file contains a matching c.9097dupA / p.(Thr3033Asnfs*11) row, but it supplies a Class 5 truncating-variant annotation rather than a pre-assigned PP3 code.
VCEP rule
Apply PP3 for missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain and predicted impact via protein change (BayesDel predicted Impact). ... Apply PP3 for predicted splicing (SpliceAI ≥0.2) for silent, missense/in-frame (irrespective of location in clinically important functional domain) and for intronic variants outside of the donor and acceptor ±1,2 positions.
Evidence considered
ENIGMA Specifications v1.2 PP3 rule: "Apply PP3 for missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain and predicted impact via protein change (BayesDel predicted Impact)."
ENIGMA Specifications v1.2 PP3 rule: "Apply PP3 for predicted splicing (SpliceAI ≥0.2) for silent, missense/in-frame (irrespective of location in clinically important functional domain) and for intronic variants outside of the donor and acceptor ±1,2 positions."
The case normalization identifies NM_000059.4:c.9097dup as NP_000050.3:p.(Thr3033AsnfsTer11) / p.(T3033Nfs*11), a frameshift, which is outside both PP3 pathways.
SupplementaryTables_V1.2_2024-11-18.xlsx, matching row: c.9097dupA; p.(Thr3033Asnfs*11); Class 5; Variant allele predicted to encode a truncated non-functional protein (ENIGMA Rules, Version 2.5.1, 29 June 2017). This row does not pre-assign PP3.
SpliceAI maximum delta score = 0.208 was not used because PP3 is upstream not_applicable for this frameshift variant.
Still missing
No exact c.9097dup, p.Thr3033AsnfsTer11, or p.T3033Nfs*11 entry was found in Specifications_V1.2_2024-11-18.docx; this does not affect the upstream frameshift-based inapplicability determination.
No exact c.9097dup, p.Thr3033AsnfsTer11, or p.T3033Nfs*11 entry was found in Appendices_V1.2_2024-11-18.docx; this does not affect the upstream frameshift-based inapplicability determination.
No exact c.9097dup, p.Thr3033AsnfsTer11, or p.T3033Nfs*11 entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf; this does not affect the upstream frameshift-based inapplicability determination.
BP1N/ANot applicable: BP1 covers silent, missense, or in-frame variants, whereas c.9097dup is a protein-terminating frameshift.
Details ▾Hide ▴
Reasoning
The ENIGMA BP1 rule applies to silent, missense, or in-frame insertion/deletion/delins variants outside a defined functional domain with no predicted splicing. This variant is a frameshift protein-termination variant, not one of those named variant types, so BP1 is outside the rule's applicability.
VCEP rule
Apply BP1_Strong for silent substitution, missense or in-frame insertion, deletion or delins variants outside a (potentially) clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1). Missense prediction not applicable.
Evidence considered
Specifications V1.2 BP1 row limits BP1_Strong to silent, missense, or in-frame insertion/deletion/delins variants outside a clinically important functional domain and requires SpliceAI ≤0.1.
Appendix J Table 16 repeats the same BP1 variant-type and no-splicing conditions.
The case consequence is p.(Thr3033AsnfsTer11), a frameshift.
BP2VCEPNot applicable: the BRCA2 VCEP explicitly says BP2 is not to be used and limits it to the BS2 context.
Details ▾Hide ▴
Reasoning
BP2 is not applicable under the BRCA2 ENIGMA VCEP specification: the criterion is explicitly marked Do not use and is applied only in the context of BS2. No BP2 evidence is therefore assigned, regardless of the reported allelic observation.
VCEP rule
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder, or observed in cis with a pathogenic variant in any inheritance pattern ... Do not use ... Applied only in the context of BS2.
Evidence considered
ENIGMA Specifications_V1.2_2024-11-18.docx, BP2 entry: observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern; the next lines state Do not use and Applied only in the context of BS2.
Still missing
Specifications_V1.2_2024-11-18.docx was searched for c.9097dup, p.Thr3033AsnfsTer11, and p.T3033Nfs*11; it contains the governing BP2 rule but no variant-specific row.
BP3VCEPNot applicable: the VCEP says not to use BP3, and this variant is a frameshift rather than an in-frame repeat-region change.
Details ▾Hide ▴
Reasoning
The ENIGMA BRCA2 specification explicitly says not to use BP3 and defines it for in-frame deletions/insertions in a repetitive region without a known function. This variant is a frameshift duplication, not an in-frame repeat-region insertion or deletion.
VCEP rule
In-frame deletions/insertions in a repetitive region without a known function ... Do not use ... Captured by bioinformatic tool prediction, and domain analysis.
Evidence considered
ENIGMA Specifications v1.2, BP3 entry: in-frame deletions/insertions in a repetitive region without a known function; the specification says Do not use and states that this is captured by bioinformatic tool prediction and domain analysis.
ClinGen ENIGMA BRCA2 CSPEC BP3 entry: applicability is Not Applicable.
BP4N/ANot applicable: ENIGMA restricts BP4 to missense/in-frame, silent, or eligible intronic variants, and c.9097dup is a frameshift.
Details ▾Hide ▴
Reasoning
NM_000059.4:c.9097dup produces a frameshift protein change. The ENIGMA BRCA2 v1.2 BP4 rule has only three pathways: missense or in-frame variants inside a clinically important domain requiring BayesDel and SpliceAI, silent variants inside such a domain requiring SpliceAI, or intronic variants outside donor/acceptor ±1,2 positions requiring SpliceAI. A frameshift is none of these variant types, so BP4 is not applicable. Consistent with the criterion scope, a no-impact splice prediction cannot provide BP4 evidence for a truncating protein consequence. The available SpliceAI maximum delta score of 0.208 is not used for BP4.
VCEP rule
Apply BP4 for: ... Missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain, and no predicted impact via protein change or splicing (BayesDel predicted No Impact AND SpliceAI ≤0.1). ... Silent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (SpliceAI ≤0.1). ... Intronic variants outside of the donor and acceptor ±1,2 positions AND no predicted impact via splicing (SpliceAI ≤0.1).
Evidence considered
ENIGMA Specifications v1.2 BP4 rule: "Missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain, and no predicted impact via protein change or splicing (BayesDel predicted No Impact AND SpliceAI ≤0.1)."
ENIGMA Specifications v1.2 BP4 rule: "Silent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (SpliceAI ≤0.1)."
ENIGMA Specifications v1.2 BP4 rule: "Intronic variants outside of the donor and acceptor ±1,2 positions AND no predicted impact via splicing (SpliceAI ≤0.1)."
The case normalization identifies NM_000059.4:c.9097dup as NP_000050.3:p.(Thr3033AsnfsTer11) / p.(T3033Nfs*11), a frameshift outside all three BP4 pathways.
SupplementaryTables_V1.2_2024-11-18.xlsx, matching row: c.9097dupA; p.(Thr3033Asnfs*11); Class 5; truncated non-functional protein annotation. This row does not pre-assign BP4.
SpliceAI maximum delta score = 0.208 was not used because BP4 is upstream not_applicable for this frameshift variant.
Still missing
No exact c.9097dup, p.Thr3033AsnfsTer11, or p.T3033Nfs*11 entry was found in Specifications_V1.2_2024-11-18.docx; this does not affect the upstream frameshift-based inapplicability determination.
No exact c.9097dup, p.Thr3033AsnfsTer11, or p.T3033Nfs*11 entry was found in Appendices_V1.2_2024-11-18.docx; this does not affect the upstream frameshift-based inapplicability determination.
No exact c.9097dup, p.Thr3033AsnfsTer11, or p.T3033Nfs*11 entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf; this does not affect the upstream frameshift-based inapplicability determination.
BP7N/ANot applicable: ENIGMA scopes BP7 to silent or eligible intronic variants, while c.9097dup is a frameshift without a BP7 RNA-assay pathway.
Details ▾Hide ▴
Reasoning
NM_000059.4:c.9097dup produces a frameshift, not a silent/synonymous or intronic variant. The ENIGMA BRCA2 v1.2 BP7 rule applies to silent variants inside a clinically important domain if BP4 is met, and to intronic variants outside conserved donor or acceptor motif positions if BP4 is met; the separate BP7 Strong RNA path requires functional mRNA transcript-profile evidence rather than an in-silico prediction. None of those BP7 variant-type or evidence pathways applies to this frameshift, so BP7 is not applicable. The available SpliceAI score is not used for BP7.
VCEP rule
Apply BP7 for ... Silent variant inside a (potentially) clinically important functional domain, IF BP4 met. ... Intronic variants located outside conserved donor or acceptor motif positions (at or beyond positions +7/-21) IF BP4 met.
Evidence considered
ENIGMA Specifications v1.2 BP7 rule: "Apply BP7 for Silent variant inside a (potentially) clinically important functional domain, IF BP4 met."
ENIGMA Specifications v1.2 BP7 rule: "Intronic variants located outside conserved donor or acceptor motif positions (at or beyond positions +7/-21) IF BP4 met."
The case normalization identifies NM_000059.4:c.9097dup as NP_000050.3:p.(Thr3033AsnfsTer11) / p.(T3033Nfs*11), a frameshift, so neither the silent nor intronic BP7 pathway applies.
SupplementaryTables_V1.2_2024-11-18.xlsx, matching row: c.9097dupA; p.(Thr3033Asnfs*11); Class 5; truncated non-functional protein annotation. This row does not pre-assign BP7.
SpliceAI maximum delta score = 0.208 was not used because BP7 is upstream not_applicable for this frameshift variant.
Still missing
No exact c.9097dup, p.Thr3033AsnfsTer11, or p.T3033Nfs*11 entry was found in Specifications_V1.2_2024-11-18.docx; this does not affect the upstream frameshift-based inapplicability determination.
No exact c.9097dup, p.Thr3033AsnfsTer11, or p.T3033Nfs*11 entry was found in Appendices_V1.2_2024-11-18.docx; this does not affect the upstream frameshift-based inapplicability determination.
No exact c.9097dup, p.Thr3033AsnfsTer11, or p.T3033Nfs*11 entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf; this does not affect the upstream frameshift-based inapplicability determination.
AF 6.2e-06 · 10 / 1,612,818 alleles · 0 hom · FAF 2.9e-06
Ashkenazi Jewish1 / 29,582
3.4e-05
Remaining individuals1 / 62,434
1.6e-05
European (non-Finnish)8 / 1,179,416
6.8e-06
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, African/African American.
gnomAD v2.1
AF 1.2e-05 · 3 / 245,952 alleles · 0 hom · FAF 3e-06
African/African American1 / 15,908
6.3e-05
European (non-Finnish)2 / 110,460
1.8e-05
0 alternate alleles recorded in 6 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.20033e-06; MAF= 0.00062%, 10/1612818 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 3.38043e-05; MAF= 0.00338%, 1/29582 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.21975e-05; MAF= 0.00122%, 3/245952 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.28615e-05; MAF= 0.00629%, 1/15908 alleles, homozygotes = 0); grpmax FAF= 3.01e-06.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
SpliceAI acceptor lossat -84 bp
0.208
SpliceAI acceptor gainat +146 bp
0.036
SpliceAI donor lossat +44 bp
0.020
SpliceAI donor gainat -37 bp
0.003
Pangolin splice lossmagnitude shown
-0.175
Pangolin splice gain
0.009
Other predictors
REVEL
Not available
BayesDel
Not available
How the predictions were used
PP3N/ANot applicable: ENIGMA limits PP3 to missense/in-frame, silent, or eligible intronic variants, whereas c.9097dup is a frameshift.
Details ▾Hide ▴
Reasoning
NM_000059.4:c.9097dup produces NP_000050.3:p.(Thr3033AsnfsTer11), a frameshift variant. The ENIGMA BRCA2 v1.2 PP3 rule defines a protein-impact pathway only for missense or in-frame insertion, deletion, or delins variants inside a clinically important functional domain, and a splice-prediction pathway only for silent, missense/in-frame, or eligible intronic variants. A frameshift is outside every PP3 variant-type pathway, so PP3 is not applicable before any predictor score is considered. The available SpliceAI maximum delta score of 0.208 is therefore not used to assign PP3. The SupplementaryTables V1.2 file contains a matching c.9097dupA / p.(Thr3033Asnfs*11) row, but it supplies a Class 5 truncating-variant annotation rather than a pre-assigned PP3 code.
VCEP rule
Apply PP3 for missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain and predicted impact via protein change (BayesDel predicted Impact). ... Apply PP3 for predicted splicing (SpliceAI ≥0.2) for silent, missense/in-frame (irrespective of location in clinically important functional domain) and for intronic variants outside of the donor and acceptor ±1,2 positions.
Evidence considered
ENIGMA Specifications v1.2 PP3 rule: "Apply PP3 for missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain and predicted impact via protein change (BayesDel predicted Impact)."
ENIGMA Specifications v1.2 PP3 rule: "Apply PP3 for predicted splicing (SpliceAI ≥0.2) for silent, missense/in-frame (irrespective of location in clinically important functional domain) and for intronic variants outside of the donor and acceptor ±1,2 positions."
The case normalization identifies NM_000059.4:c.9097dup as NP_000050.3:p.(Thr3033AsnfsTer11) / p.(T3033Nfs*11), a frameshift, which is outside both PP3 pathways.
SupplementaryTables_V1.2_2024-11-18.xlsx, matching row: c.9097dupA; p.(Thr3033Asnfs*11); Class 5; Variant allele predicted to encode a truncated non-functional protein (ENIGMA Rules, Version 2.5.1, 29 June 2017). This row does not pre-assign PP3.
SpliceAI maximum delta score = 0.208 was not used because PP3 is upstream not_applicable for this frameshift variant.
Still missing
No exact c.9097dup, p.Thr3033AsnfsTer11, or p.T3033Nfs*11 entry was found in Specifications_V1.2_2024-11-18.docx; this does not affect the upstream frameshift-based inapplicability determination.
No exact c.9097dup, p.Thr3033AsnfsTer11, or p.T3033Nfs*11 entry was found in Appendices_V1.2_2024-11-18.docx; this does not affect the upstream frameshift-based inapplicability determination.
No exact c.9097dup, p.Thr3033AsnfsTer11, or p.T3033Nfs*11 entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf; this does not affect the upstream frameshift-based inapplicability determination.
BP4N/ANot applicable: ENIGMA restricts BP4 to missense/in-frame, silent, or eligible intronic variants, and c.9097dup is a frameshift.
Details ▾Hide ▴
Reasoning
NM_000059.4:c.9097dup produces a frameshift protein change. The ENIGMA BRCA2 v1.2 BP4 rule has only three pathways: missense or in-frame variants inside a clinically important domain requiring BayesDel and SpliceAI, silent variants inside such a domain requiring SpliceAI, or intronic variants outside donor/acceptor ±1,2 positions requiring SpliceAI. A frameshift is none of these variant types, so BP4 is not applicable. Consistent with the criterion scope, a no-impact splice prediction cannot provide BP4 evidence for a truncating protein consequence. The available SpliceAI maximum delta score of 0.208 is not used for BP4.
VCEP rule
Apply BP4 for: ... Missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain, and no predicted impact via protein change or splicing (BayesDel predicted No Impact AND SpliceAI ≤0.1). ... Silent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (SpliceAI ≤0.1). ... Intronic variants outside of the donor and acceptor ±1,2 positions AND no predicted impact via splicing (SpliceAI ≤0.1).
Evidence considered
ENIGMA Specifications v1.2 BP4 rule: "Missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain, and no predicted impact via protein change or splicing (BayesDel predicted No Impact AND SpliceAI ≤0.1)."
ENIGMA Specifications v1.2 BP4 rule: "Silent variant inside a (potentially) clinically important functional domain, if no predicted impact via splicing (SpliceAI ≤0.1)."
ENIGMA Specifications v1.2 BP4 rule: "Intronic variants outside of the donor and acceptor ±1,2 positions AND no predicted impact via splicing (SpliceAI ≤0.1)."
The case normalization identifies NM_000059.4:c.9097dup as NP_000050.3:p.(Thr3033AsnfsTer11) / p.(T3033Nfs*11), a frameshift outside all three BP4 pathways.
SupplementaryTables_V1.2_2024-11-18.xlsx, matching row: c.9097dupA; p.(Thr3033Asnfs*11); Class 5; truncated non-functional protein annotation. This row does not pre-assign BP4.
SpliceAI maximum delta score = 0.208 was not used because BP4 is upstream not_applicable for this frameshift variant.
Still missing
No exact c.9097dup, p.Thr3033AsnfsTer11, or p.T3033Nfs*11 entry was found in Specifications_V1.2_2024-11-18.docx; this does not affect the upstream frameshift-based inapplicability determination.
No exact c.9097dup, p.Thr3033AsnfsTer11, or p.T3033Nfs*11 entry was found in Appendices_V1.2_2024-11-18.docx; this does not affect the upstream frameshift-based inapplicability determination.
No exact c.9097dup, p.Thr3033AsnfsTer11, or p.T3033Nfs*11 entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf; this does not affect the upstream frameshift-based inapplicability determination.
BP7N/ANot applicable: ENIGMA scopes BP7 to silent or eligible intronic variants, while c.9097dup is a frameshift without a BP7 RNA-assay pathway.
Details ▾Hide ▴
Reasoning
NM_000059.4:c.9097dup produces a frameshift, not a silent/synonymous or intronic variant. The ENIGMA BRCA2 v1.2 BP7 rule applies to silent variants inside a clinically important domain if BP4 is met, and to intronic variants outside conserved donor or acceptor motif positions if BP4 is met; the separate BP7 Strong RNA path requires functional mRNA transcript-profile evidence rather than an in-silico prediction. None of those BP7 variant-type or evidence pathways applies to this frameshift, so BP7 is not applicable. The available SpliceAI score is not used for BP7.
VCEP rule
Apply BP7 for ... Silent variant inside a (potentially) clinically important functional domain, IF BP4 met. ... Intronic variants located outside conserved donor or acceptor motif positions (at or beyond positions +7/-21) IF BP4 met.
Evidence considered
ENIGMA Specifications v1.2 BP7 rule: "Apply BP7 for Silent variant inside a (potentially) clinically important functional domain, IF BP4 met."
ENIGMA Specifications v1.2 BP7 rule: "Intronic variants located outside conserved donor or acceptor motif positions (at or beyond positions +7/-21) IF BP4 met."
The case normalization identifies NM_000059.4:c.9097dup as NP_000050.3:p.(Thr3033AsnfsTer11) / p.(T3033Nfs*11), a frameshift, so neither the silent nor intronic BP7 pathway applies.
SupplementaryTables_V1.2_2024-11-18.xlsx, matching row: c.9097dupA; p.(Thr3033Asnfs*11); Class 5; truncated non-functional protein annotation. This row does not pre-assign BP7.
SpliceAI maximum delta score = 0.208 was not used because BP7 is upstream not_applicable for this frameshift variant.
Still missing
No exact c.9097dup, p.Thr3033AsnfsTer11, or p.T3033Nfs*11 entry was found in Specifications_V1.2_2024-11-18.docx; this does not affect the upstream frameshift-based inapplicability determination.
No exact c.9097dup, p.Thr3033AsnfsTer11, or p.T3033Nfs*11 entry was found in Appendices_V1.2_2024-11-18.docx; this does not affect the upstream frameshift-based inapplicability determination.
No exact c.9097dup, p.Thr3033AsnfsTer11, or p.T3033Nfs*11 entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf; this does not affect the upstream frameshift-based inapplicability determination.
SpliceAI predicts possible splice impact for this variant (max delta score = 0.21).
9 paper records listed. 2 cited in the classification.
Cited in the classification
Hepatoblastoma in a 4-year-old girl with Fanconi anaemia.
Kopic S et al. · 2011 May
The paper explicitly reports BRCA2 c.9097dupA as a one-base duplication causing a frameshift and premature protein truncation, p.T3033NfsX10, in a compound-heterozygous BRCA2/FANCD1 case; this is equivalent to the normalized p.(Thr3033AsnfsTer11) notation.
→ PVS1 · very strong→ PM3 · moderateNames this variant
Subsequent DNA sequencing revealed biallelic mutations in the corresponding gene. They included the missense substitution c.7878G>C (p.W2626C) and the 1-bp duplication c.9097dupA leading to frameshift and premature protein truncation (p.T3033NfsX10) (Fig. 3D, upper and lower panel, respectively).
Location Case Report, paragraph describing BRCA2 sequencing
Context Single-patient case report with BRCA2 DNA sequencing and fibroblast assays including mitomycin-C-induced cell-cycle analysis, FANCD2/FANCJ/FANCN immunoblotting, and RAD51-focus formation.
Prevalence of BRCA1 and BRCA2 germline mutations in patients with triple-negative breast cancer.
Wong-Brown MW et al. · 2015 Feb
The paper reports the exact BRCA2 c.9097dup / p.Thr3033Asnfs*11 variant in exon 23 and classifies it as a BIC class 5 pathogenic mutation in a Polish triple-negative breast cancer cohort.
23 c.9097dup p.Thr3033Asnfs*11 rs80359747 Y/class 5—pathogenic 285,224 68 N
Location Table 2, Polish cohort, BRCA2 exon 23
Context Germline sequencing of BRCA1 and BRCA2 coding exons and exon-intron boundaries in 335 Polish patients with triple-negative breast cancer using Fluidigm Access Array PCR amplification and Illumina MiSeq sequencing.
Other recorded publications
Truncated BRCA2 is cytoplasmic: implications for cancer-linked mutations.
Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.20033e-06; MAF= 0.00062%, 10/1612818 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 3.38043e-05; MAF= 0.00338%, 1/29582 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.21975e-05; MAF= 0.00122%, 3/245952 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.28615e-05; MAF= 0.00629%, 1/15908 alleles, homozygotes = 0); grpmax FAF= 3.01e-06.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Pathogenic (45 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel). (ClinVarID = 38208)
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.21).
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV66447774, n = 25 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.