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BRCA2c.8107dupPathogenic
Print report
Variant interpretation report

BRCA2 c.8107dup, p.(Thr2703AsnfsTer3)

NM_000059.4:c.8107dup NP_000050.3:p.(Thr2703AsnfsTer3) Frameshift · exon 18 View identifiers
Classification
Pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.

Pathogenic.A pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

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.

NCBI Gene ↗ OncoKB ↗
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.

Pathogenic evidence criteria: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong

Met, very strong: c.8107dup is an exon 18 frameshift with a premature stop at p.2705, upstream of the VCEP's c.9600 NMD escape boundary.

PM5Strong
PM5 · strong

Met, Strong: ENIGMA Table 4 preassigns PM5_Strong (PTC) to BRCA2 exon 18, where this genomic frameshift creates a premature termination codon.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Pathogenic

Pathogenic: PVS1 (very strong) plus PM5 (strong) satisfies the ENIGMA BRCA2 Table 3 combination rule.

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
Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

No listed criterion applied
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.045 maximum delta

Recorded SpliceAI maximum delta score: 0.045. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen BRCA2 VCEP v1.2, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 0 not met · 11 not assessed · 15 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

PVS1 is met at very strong strength for the exon 18 frameshift, while PM4 and BP3 are not applicable under the VCEP's explicit criterion rules.

All three requested criteria are not_applicable because the variant is a frameshift and the ENIGMA v1.2 PP3, BP4, and BP7 scopes do not include frameshift variants.

The available SpliceAI result was not double-counted or used outside the governing criterion scopes.

Met · 2

PVS1 Very strongVCEPMet, very strong: c.8107dup is an exon 18 frameshift with a premature stop at p.2705, upstream of the VCEP's c.9600 NMD escape boundary. Details ▾Hide ▴
Reasoning

NM_000059.4:c.8107dup is a frameshift producing NP_000050.3:p.(Thr2703AsnfsTer3), a premature termination codon at predicted protein position 2705 in the BRCA2 transcript. The VCEP identifies loss of function as a well-established BRCA2 disease mechanism and includes frameshift variants in its PVS1 rule. The variant is in BRCA2 exon 18 according to the ENIGMA Table 4 exon map. Table 4 assigns PVS1 to BRCA2 exon 18 PTC variants, and Appendix D states that BRCA2 PTCs from c.9600 onward are not predicted to result in NMD; c.8107 is upstream of that boundary. Therefore the full, un-downgraded PVS1 strength applies. The variant was not found as a variant-specific entry in Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, Specifications_Table4_V1.2_2024-11-18.xlsx, or PMID_22505045_Houdayer_2012_HumMutat.pdf; the governing exon-level Table 4 pre-assignment was used instead.

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). ... PTC from position c.9600 onwards are not predicted to result in NMD.
Evidence considered
  • Case normalization: NM_000059.4:c.8107dup produces NP_000050.3:p.(Thr2703AsnfsTer3), also p.(T2703Nfs*3), with consequence class frameshift.
  • ENIGMA Specifications Table 4, BRCA2 E18 row: PVS1 is assigned for protein-termination-codon variants; the row's PTC column is PVS1.
  • ENIGMA Specifications v1.2, PVS1 criterion: null variants including frameshift variants in a gene where loss of function is a known disease mechanism are evaluated according to the PVS1 flowchart and Table 4.
  • ENIGMA Appendix D: BRCA2 loss of function is a well-established disease mechanism; Figure 5 states that PTC from c.9600 onwards are not predicted to result in NMD. c.8107 is upstream of c.9600.
  • The three requested variant notations were searched in all four named governing full-text files; no variant-specific entry was found.
Still missing
  • No variant-specific entry for c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 was found in Specifications_V1.2_2024-11-18.docx.
  • No variant-specific entry for c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 was found in Appendices_V1.2_2024-11-18.docx.
  • No variant-specific entry for c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 was found in Specifications_Table4_V1.2_2024-11-18.xlsx; the applicable BRCA2 exon 18 row was present and used.
  • No variant-specific entry for c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗vcep_specifications_table4_v1_2_2024_11_18 ↗
PM5 StrongVCEPMet, Strong: ENIGMA Table 4 preassigns PM5_Strong (PTC) to BRCA2 exon 18, where this genomic frameshift creates a premature termination codon. Details ▾Hide ▴
Reasoning

The variant is a genomic protein-termination frameshift in BRCA2 exon 18. ENIGMA Table 4 assigns the BRCA2 E18 PTC row PM5_Strong (PTC), and the row is not one of the excluded PM5_N/A exons. This is the VCEP's pre-assigned exon-specific governing code for additional weight to a PVS1-annotated PTC; no classic same-residue missense PM5 inference is used.

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. Only applied to genomic PTC changes (not splicing). Weight determined by exon where the nucleotide change occurs.
Evidence considered
  • Variant normalization identifies NM_000059.4:c.8107dup as a frameshift producing p.(Thr2703AsnfsTer3) / p.(T2703Nfs*3), a genomic PTC consequence.
  • Specifications_Table4_V1.2_2024-11-18.xlsx, BRCA2 E18 row: PVS1 | PTC | PM5_Strong (PTC).
  • ENIGMA Specifications v1.2 states that PM5_VariableWeight (PTC) is for a PTC variant in an exon where a different proven pathogenic PTC variant has been seen, is used for additional weight for PVS1-annotated PTC variants, applies only to genomic PTC changes, and is weighted by exon.
  • The three requested variant notations were searched in the four governing VCEP full-text files; Table 4 supplied the applicable exon-level pre-assigned code rather than an exact variant row.
Still missing
  • No exact c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in Specifications_V1.2_2024-11-18.docx.
  • No exact c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in Appendices_V1.2_2024-11-18.docx.
  • No exact c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx; the governing BRCA2 E18 exon row was found instead.
  • No exact c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.
Sources
vcep_specifications_table4_v1_2_2024_11_18 ↗vcep_specifications_v1_2_2024_11_18 ↗cspec ↗

Not assessed · 11 · no assessment recorded

PS3 VCEPNot assessed: no variant-specific calibrated assay result or pre-assigned PS3 code was found for BRCA2 c.8107dup in the governing ENIGMA sources. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP reserves PS3 for well-established in vitro or in vivo functional studies showing a damaging effect, with protein-only or combined mRNA-and-protein assays evaluated through calibrated recommendations in Table 9. The exact variant was not found under c.8107dup, p.(Thr2703AsnfsTer3), or p.(T2703Nfs*3) in Specifications_Table9_V1.2_2024-11-18.xlsx, SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, or HUMU-40-1557-s001.xlsx. The extracted functional publications describe other BRCA2 variants or gene-level mechanisms and do not provide variant-specific assay data for c.8107dup. Therefore, no VCEP-governed PS3 evidence or calibrated strength can be assigned.

VCEP rule
Well-established in vitro or in vivo functional studies supportive of a damaging effect Assay measures effect via protein only OR mRNA and protein combined. See Appendix E See Figure 1C for simplified flowchart/s to advise application of codes for functional data, in content of variant type and location within a (potentially) clinically important functional domain. See Table 9, provided as a separate excel spreadsheet, for a comprehensive table of applicable codes using published calibrated functional assay results.
Evidence considered
  • ENIGMA Specifications v1.2, PS3 functional-assay rule: protein-only or combined mRNA-and-protein assays showing a damaging effect are eligible, with calibrated recommendations in Table 9.
  • ENIGMA Specifications Table 9 search: no row matched BRCA2 c.8107dup, p.(Thr2703AsnfsTer3), or p.(T2703Nfs*3).
  • The reviewed functional publications PMID:22193408, PMID:24312913, PMID:11239455, PMID:10570174, and PMID:20878484 did not mention this variant; their assays or observations concerned other BRCA2 variants or gene-level mechanisms.
Still missing
  • No entry for c.8107dup, p.(Thr2703AsnfsTer3), or p.(T2703Nfs*3) in SupplementaryTables_V1.2_2024-11-18.xlsx.
  • No entry for c.8107dup, p.(Thr2703AsnfsTer3), or p.(T2703Nfs*3) in Specifications_V1.2_2024-11-18.docx.
  • No entry for c.8107dup, p.(Thr2703AsnfsTer3), or p.(T2703Nfs*3) in Appendices_V1.2_2024-11-18.docx.
  • No entry for c.8107dup, p.(Thr2703AsnfsTer3), or p.(T2703Nfs*3) in HUMU-40-1557-s001.xlsx.
  • No entry for c.8107dup, p.(Thr2703AsnfsTer3), or p.(T2703Nfs*3) in Specifications_Table9_V1.2_2024-11-18.xlsx.
  • No variant-specific functional assay result for c.8107dup is reported in the reviewed functional publications.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗vcep_specifications_table9_v1_2_2024_11_18 ↗vcep_supplementarytables_v1_2_2024_11_18 ↗vcep_humu_40_1557_s001 ↗PMID:22193408 ↗PMID:24312913 ↗PMID:11239455 ↗PMID:10570174 ↗PMID:20878484 ↗
PS4 VCEPNot assessed: no variant-specific case-control p-value, odds ratio, and confidence interval were available to evaluate the ENIGMA PS4 requirements. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 rule requires case-control evidence with p-value <=0.05, OR >=4, and a lower confidence interval excluding 2.0. No variant-specific case-control result for NM_000059.4:c.8107dup / p.(Thr2703AsnfsTer3) / p.(T2703Nfs*3) was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt, HUMU-40-1557-s001.xlsx.txt, or Specifications_V1.2_2024-11-18.docx.txt. The VCEP also states not to use Proband Counting as originally described, so the available variant-specific OncoKB context and gene-level papers cannot establish PS4.

VCEP rule
The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls. Case-control studies; p-value ≤0.05 and OR ≥4 (lower confidence interval excludes 2.0).
Evidence considered
  • Searched SupplementaryTables_V1.2_2024-11-18.xlsx.txt for c.8107dup, p.Thr2703AsnfsTer3, and p.T2703Nfs*3; no matching entry was found.
  • Searched HUMU-40-1557-s001.xlsx.txt for c.8107dup, p.Thr2703AsnfsTer3, and p.T2703Nfs*3; no matching entry was found.
  • Searched Specifications_V1.2_2024-11-18.docx.txt for c.8107dup, p.Thr2703AsnfsTer3, and p.T2703Nfs*3; no matching entry was found.
  • The available OncoKB record reports variant-specific likely oncogenic / likely loss-of-function context but does not provide the ENIGMA PS4 case-control inputs.
Still missing
  • No entry for c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No entry for c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 in HUMU-40-1557-s001.xlsx.txt.
  • No entry for c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 in Specifications_V1.2_2024-11-18.docx.txt.
  • A variant-specific case-control p-value, odds ratio, and confidence interval are unavailable.
Sources
cspec ↗vcep_supplementarytables_v1_2_2024_11_18 ↗vcep_humu_40_1557_s001 ↗PMID:31131967 ↗vcep_specifications_v1_2_2024_11_18 ↗
PM3 VCEPNot assessed: no Fanconi Anemia phenotype, BRCA2 co-variant, phase, or PM3 point observations are available for this variant. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 rule requires a patient with a phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia and co-occurrent variants in the same gene, with phase and the co-occurrent variant's VCEP classification used to assign points. The available case evidence contains no affected-proband Fanconi Anemia phenotype, chromosome-breakage result, pathogenic/likely pathogenic BRCA2 co-variant, or phase observation for NM_000059.4:c.8107dup; therefore PM3 cannot be assessed.

VCEP rule
Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene. ... Variant under assessment must be sufficiently rare (not meeting a benign population evidence code). ... See Table 6 for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points. ... PM3_Strong = 4 (or more) points; PM3 = 2 points; PM3_Supporting = 1 point.
Evidence considered
  • Specifications_V1.2_2024-11-18.docx, Table 6: PM3 scoring requires a BRCA2-related Fanconi Anemia presentation and assigns 2 points for a P/LP variant in trans or homozygote, 1 point when phase is unknown; final PM3 is based on the summed points.
  • The case evidence bundle contains no observation documenting Fanconi Anemia phenotype, chromosome breakage, an in-trans or homozygous pathogenic/likely pathogenic BRCA2 variant, or phase for NM_000059.4:c.8107dup.
  • The governing full-text file was searched under c.8107dup, p.Thr2703AsnfsTer3, and p.T2703Nfs*3; no variant-specific entry was found.
Still missing
  • No affected-proband Fanconi Anemia phenotype or chromosome-breakage result was available.
  • No pathogenic or likely pathogenic BRCA2 co-variant and no phase determination were available.
  • Specifications_V1.2_2024-11-18.docx.txt was searched for c.8107dup, p.Thr2703AsnfsTer3, and p.T2703Nfs*3; no entry for this variant was found.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
PP1 VCEPNot assessed: no quantitative co-segregation LR or affected-family segregation data is available to compare with the PP1 threshold of LR ≥2.08:1. Details ▾Hide ▴
Reasoning

The VCEP requires multiple affected family members and a quantitative co-segregation analysis with an LR threshold of at least 2.08:1 for PP1 Supporting, 4.3:1 for Moderate, 18.7:1 for Strong, or 350:1 for Very Strong. The case materials contain no proband-level family segregation data, meioses, parental testing, or quantitative co-segregation LR for c.8107dup; the three governing VCEP files were searched under c.8107dup, p.Thr2703AsnfsTer3, and p.T2703Nfs*3 without a matching entry. PP1 therefore cannot be assessed.

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
  • ENIGMA BRCA2 Specification v1.2, PP1_VariableWeight: co-segregation with disease in multiple affected family members, quantified by a co-segregation method; PP1 Supporting requires LR ≥2.08:1, Moderate LR ≥4.3:1, Strong LR ≥18.7:1, and Very Strong LR ≥350:1.
  • The case bundle provides no affected-family segregation observations, parental testing, meioses, or quantitative co-segregation LR for NM_000059.4:c.8107dup.
  • The on-record VCEP files were searched under c.8107dup, p.Thr2703AsnfsTer3, and p.T2703Nfs*3; no matching variant entry was found in any of the three named files.
Still missing
  • No proband-level pedigree, affected-relative genotypes, meioses, parental testing, or quantitative co-segregation LR is available.
  • No entry for c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No entry for c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 was found in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗PMID:10570174 ↗PMID:11239455 ↗PMID:20878484 ↗PMID:22193408 ↗PMID:24312913 ↗
PP4 VCEPNot assessed: the required BRCA2 clinical-history table has no row for this variant, so no combined clinical likelihood ratio can be compared with PP4 thresholds. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 rule permits PP4 only for combined clinically calibrated likelihood-ratio evidence toward pathogenicity, with PP4 Supporting at LR >=2.08:1, Moderate at LR >=4.3:1, Strong at LR >=18.7:1, and Very Strong at LR >=350:1. The required BRCA2 clinical-history table was searched under all three supplied variant notations and has no row for this variant, so no applicable combined clinical LR is available.

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
Evidence considered
  • Searched PMID_31853058_BRCA2_clinical_history_LR.xlsx.txt for c.8107dup, p.Thr2703AsnfsTer3, and p.T2703Nfs*3; no matching BRCA2 row was found.
  • No variant-level LR from Li et al. 2020 was available; the article and methods supplement are methodology sources, not substitutes for the gene-specific variant row.
Still missing
  • No entry for c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 in PMID_31853058_BRCA2_clinical_history_LR.xlsx.txt.
  • No combined clinically calibrated LR is available for this variant.
Sources
cspec ↗vcep_pmid_31853058_brca2_clinical_history_lr ↗PMID:31853058 ↗
BA1 VCEPNot assessed: the variant is absent from both required non-cancer datasets, but FAF, read depth, and quality-control values needed for BA1 are unavailable. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 v1.2 BA1 rule requires FAF >0.001 in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes, with read depth >=20 and exclusion of failed-QC data. The case evidence reports the variant absent from GNOMAD_V2_1_NON_CANCER and GNOMAD_V3_1_NON_CANCER, but provides no FAF, read-depth, or QC values. Therefore the threshold and depth safeguards cannot be evaluated from the available evidence, so BA1 is not assessed.

VCEP rule
Stand-alone allele frequency. ... Above 0.001 (0.1%) ... Apply based on maximum filter allele frequency observed in a gnomAD non-founder population, considering exome and genome data separately. Do not apply if read depth <20. Do not apply to well-established pathogenic founder variants. Exclude data if variant failed quality control filter.
Evidence considered
  • GNOMAD_V2_1_NON_CANCER: absent for genomic query 13-32937443-G-GA; source_data is empty, so no FAF, depth, or QC value is available.
  • GNOMAD_V3_1_NON_CANCER: absent for genomic query 13-32363306-G-GA; source_data is empty, so no FAF, depth, or QC value is available.
  • ENIGMA BRCA2 Specifications v1.2, BA1: the governing threshold is FAF >0.001, applied to the maximum filter allele frequency in separate exome and genome datasets, only when read depth is not <20 and the variant has not failed QC.
  • ENIGMA BRCA2 Appendices v1.2, Appendix G: BA1 uses filter allele frequency and requires read depth >20; indel-specific depth and sequencing-quality assessment are recommended.
Still missing
  • No FAF, regional read-depth, or explicit quality-control value is available for GNOMAD_V2_1_NON_CANCER or GNOMAD_V3_1_NON_CANCER.
  • No variant-specific entry was found after searching SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, and HUMU-40-1557-s001.xlsx.txt for c.8107dup, p.Thr2703AsnfsTer3, and p.T2703Nfs*3.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗gnomad_v2 ↗
BS1 VCEPNot assessed: both required non-cancer datasets report absence, but FAF, read depth, and quality-control values needed for BS1 are unavailable. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 v1.2 BS1 rule requires FAF >0.0001 for BS1 Strong or >0.00002 to <=0.0001 for BS1 Supporting in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes, with read depth >=20 and exclusion of failed-QC data. The variant is reported absent from both required non-cancer datasets, but no FAF, read-depth, or QC values are supplied. The BS1 thresholds and safeguards therefore cannot be evaluated, so BS1 is not assessed.

VCEP rule
Allele frequency greater than expected for disease. ... BS1 - above 0.0001 (0.01%) BS1_Supporting - >0.00002 (0.002%) to ≤ 0.0001 (0.01%). ... Apply based on maximum filter allele frequency in a gnomAD non-founder population, considering exome and genome data separately. Do not apply if read depth <20. Do not apply to well-established pathogenic founder variants. Exclude data if variant failed quality control filter.
Evidence considered
  • GNOMAD_V2_1_NON_CANCER: absent for genomic query 13-32937443-G-GA; source_data is empty, so no FAF, depth, or QC value is available.
  • GNOMAD_V3_1_NON_CANCER: absent for genomic query 13-32363306-G-GA; source_data is empty, so no FAF, depth, or QC value is available.
  • ENIGMA BRCA2 Specifications v1.2, BS1: BS1 Strong requires FAF >0.0001; BS1 Supporting requires FAF >0.00002 and <=0.0001, using the maximum filter allele frequency in separate exome and genome datasets, subject to read-depth and QC safeguards.
  • ENIGMA BRCA2 Appendices v1.2, Appendix G: BS1 uses the highest filter allele frequency in a non-founder population, assessing exome and genome data separately, with read depth >20.
Still missing
  • No FAF, regional read-depth, or explicit quality-control value is available for GNOMAD_V2_1_NON_CANCER or GNOMAD_V3_1_NON_CANCER.
  • No variant-specific entry was found after searching SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, and HUMU-40-1557-s001.xlsx.txt for c.8107dup, p.Thr2703AsnfsTer3, and p.T2703Nfs*3.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗gnomad_v2 ↗
BS2 VCEPNot assessed: no qualifying healthy-adult observation or ENIGMA BS2 point assignment is available for this variant. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 v1.2 BS2 rule requires observation in a healthy adult for a fully penetrant disorder and applies the BRCA2-specific Fanconi Anemia stipulations and point system. The available case evidence contains no qualifying healthy-adult heterozygote, homozygote, or hemizygote observation and no BS2 point assignment. BS2 is therefore not assessed.

VCEP rule
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age ... 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 Specifications v1.2, BS2: application is based on absence of Fanconi Anemia features and requires assignment from the BS2-related point system in Specifications Table 8.
  • ENIGMA BRCA2 Specifications v1.2, Table 8: final BS2 is assigned from accumulated points, with BS2 = 4 or more points, BS2_Moderate = 2 points, and BS2_Supporting = 1 point.
  • The case evidence contains no qualifying healthy-adult observation, zygosity, phenotype, or point total for this variant.
Still missing
  • No qualifying healthy-adult clinical or research-cohort observations, zygosity, age, penetrance context, or BS2 points are available.
  • No variant-specific entry was found after searching SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, and HUMU-40-1557-s001.xlsx.txt for c.8107dup, p.Thr2703AsnfsTer3, and p.T2703Nfs*3.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗
BS3 VCEPNot assessed: no variant-specific calibrated assay result or pre-assigned BS3 code was found for BRCA2 c.8107dup in the governing ENIGMA sources. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP reserves BS3 for well-established in vitro or in vivo functional studies showing no damaging effect on protein function, using protein-only or combined mRNA-and-protein assays and calibrated recommendations in Table 9. The exact variant was not found under c.8107dup, p.(Thr2703AsnfsTer3), or p.(T2703Nfs*3) in Specifications_Table9_V1.2_2024-11-18.xlsx, SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, or HUMU-40-1557-s001.xlsx. The extracted functional publications describe other BRCA2 variants or gene-level mechanisms and do not provide variant-specific benign functional data for c.8107dup. Therefore, no VCEP-governed BS3 evidence or calibrated strength can be assigned.

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 Appendix E. See Figure 1C for process to apply codes for splicing data, in content of variant type and location. See Table 9, provided as a separate excel spreadsheet, for a comprehensive table of applicable codes using published calibrated functional assay results.
Evidence considered
  • ENIGMA Specifications v1.2, BS3 functional-assay rule: protein-only or combined mRNA-and-protein assays showing no damaging effect on protein function are eligible, with calibrated recommendations in Table 9.
  • ENIGMA Specifications Table 9 search: no row matched BRCA2 c.8107dup, p.(Thr2703AsnfsTer3), or p.(T2703Nfs*3).
  • The reviewed functional publications PMID:22193408, PMID:24312913, PMID:11239455, PMID:10570174, and PMID:20878484 did not mention this variant; their assays or observations concerned other BRCA2 variants or gene-level mechanisms.
Still missing
  • No entry for c.8107dup, p.(Thr2703AsnfsTer3), or p.(T2703Nfs*3) in SupplementaryTables_V1.2_2024-11-18.xlsx.
  • No entry for c.8107dup, p.(Thr2703AsnfsTer3), or p.(T2703Nfs*3) in Specifications_V1.2_2024-11-18.docx.
  • No entry for c.8107dup, p.(Thr2703AsnfsTer3), or p.(T2703Nfs*3) in Appendices_V1.2_2024-11-18.docx.
  • No entry for c.8107dup, p.(Thr2703AsnfsTer3), or p.(T2703Nfs*3) in HUMU-40-1557-s001.xlsx.
  • No entry for c.8107dup, p.(Thr2703AsnfsTer3), or p.(T2703Nfs*3) in Specifications_Table9_V1.2_2024-11-18.xlsx.
  • No variant-specific functional assay result for c.8107dup is reported in the reviewed functional publications.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗vcep_specifications_table9_v1_2_2024_11_18 ↗vcep_supplementarytables_v1_2_2024_11_18 ↗vcep_humu_40_1557_s001 ↗PMID:22193408 ↗PMID:24312913 ↗PMID:11239455 ↗PMID:10570174 ↗PMID:20878484 ↗
BS4 VCEPNot assessed: no quantitative non-segregation LR or affected-family data is available to compare with the BS4 Supporting threshold of LR ≤0.48:1. Details ▾Hide ▴
Reasoning

The VCEP requires lack of segregation in affected family members measured by a quantitative co-segregation method, with BS4 Supporting at LR ≤0.48:1, Moderate at LR ≤0.23:1, Strong at LR ≤0.05:1, and Very Strong at LR ≤0.00285:1. The case materials contain no non-segregating affected relatives, pedigree-level observations, parental testing, or quantitative co-segregation LR for c.8107dup; the three governing VCEP files were searched under c.8107dup, p.Thr2703AsnfsTer3, and p.T2703Nfs*3 without a matching entry. BS4 therefore cannot be assessed.

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
  • ENIGMA BRCA2 Specification v1.2, BS4_VariableWeight: lack of segregation in affected members of a family, quantified by a co-segregation method; BS4 Supporting requires LR ≤0.48:1, Moderate LR ≤0.23:1, Strong LR ≤0.05:1, and Very Strong LR ≤0.00285:1.
  • The case bundle provides no affected-family non-segregation observations, parental testing, meioses, or quantitative co-segregation LR for NM_000059.4:c.8107dup.
  • The on-record VCEP files were searched under c.8107dup, p.Thr2703AsnfsTer3, and p.T2703Nfs*3; no matching variant entry was found in any of the three named files.
Still missing
  • No affected-relative non-segregation observations, pedigree, parental testing, meioses, or quantitative co-segregation LR is available.
  • No entry for c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No entry for c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 was found in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗PMID:10570174 ↗PMID:11239455 ↗PMID:20878484 ↗PMID:22193408 ↗PMID:24312913 ↗
BP5 VCEPNot assessed: no variant-level combined clinical likelihood ratio was found for comparison with the ENIGMA BP5 <=0.48:1 supporting threshold. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 rule requires combined clinically calibrated likelihood-ratio evidence against pathogenicity, with BP5 Supporting at LR <=0.48:1, Moderate at LR <=0.23:1, Strong at LR <=0.05:1, and Very Strong at LR <=0.00285:1. The BRCA2 clinical-history LR table was searched under c.8107dup, p.Thr2703AsnfsTer3, and p.T2703Nfs*3, but no variant row or combined clinical LR was found.

VCEP rule
Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data. BP5 - LR ≤0.48 to >0.23:1
Evidence considered
  • Searched PMID_31853058_BRCA2_clinical_history_LR.xlsx.txt for c.8107dup, p.Thr2703AsnfsTer3, and p.T2703Nfs*3; no matching BRCA2 row was found.
  • No variant-level LR from Li et al. 2020 was available for BP5 evaluation.
Still missing
  • No entry for c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 in PMID_31853058_BRCA2_clinical_history_LR.xlsx.txt.
  • No combined clinically calibrated LR against pathogenicity is available for this variant.
Sources
cspec ↗vcep_pmid_31853058_brca2_clinical_history_lr ↗PMID:31853058 ↗
Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/ANot applicable: c.8107dup is a frameshift, whereas the VCEP PS1 paths require a predicted missense substitution or a matched splicing event. Details ▾Hide ▴
Reasoning

PS1 is not applicable because NM_000059.4:c.8107dup is a frameshift producing p.(Thr2703AsnfsTer3), not a predicted missense substitution, and no same predicted splicing event is established. The VCEP PS1 rule is limited to predicted missense substitutions or exonic/intronic variants with the same predicted splicing impact as a previously classified pathogenic variant.

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, for exonic and intronic variants with same predicted impact on splicing, as a previously classified pathogenic variant.
Evidence considered
  • Variant normalization: NM_000059.4:c.8107dup produces NP_000050.3:p.(Thr2703AsnfsTer3) / p.(T2703Nfs*3), classified in the case evidence as a frameshift.
  • ENIGMA Specifications v1.2 PS1 rule: the missense path requires a predicted missense substitution, while the alternative path requires an exonic or intronic variant with the same predicted impact on splicing as a previously classified pathogenic variant; neither path fits this frameshift.
  • The three requested variant notations were searched in the four governing VCEP full-text files; no exact variant entry was found.
Still missing
  • No exact c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in Specifications_V1.2_2024-11-18.docx.
  • No exact c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in Appendices_V1.2_2024-11-18.docx.
  • No exact c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.
  • No exact c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.
Sources
vcep_specifications_v1_2_2024_11_18 ↗cspec ↗
PS2 VCEPNot applicable: the VCEP says de novo occurrences lack calibrated predictive capacity for BRCA1/2-related cancers and explicitly says not to use PS2. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP explicitly designates PS2 as not applicable and states that BRCA1/2-related cancers occur relatively commonly, with no information to calibrate the predictive capacity of de novo occurrences. Therefore, PS2 is not used regardless of whether de novo testing is reported.

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
  • ENIGMA BRCA2 Specification v1.2, Table 1/criterion entry for PS2: PS2 is marked Do not use because BRCA1/2-related cancers occur relatively commonly and no information calibrates the predictive capacity of de novo occurrences.
Still missing
  • No PS2 assessment is permitted under the ENIGMA BRCA2 VCEP specification.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
PM1 VCEPNot applicable: residue 2703 lies within the DNA-binding domain aa 2481-3186, but ENIGMA explicitly says PM1 is not used. Details ▾Hide ▴
Reasoning

PM1 is not applicable under ENIGMA BRCA2 v1.2: the specification explicitly says not to use PM1 and to consider it as a component of the PP3/BP4 bioinformatic analysis. The frameshift begins at residue 2703, which lies within the VCEP-defined BRCA2 DNA-binding domain aa 2481-3186, but that domain overlap does not reinstate a criterion the VCEP excludes. The case vcep_materials.json domain_tables key is empty; the VCEP text nevertheless defines the DNA-binding domain as aa 2481-3186.

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
  • ENIGMA Specifications v1.2 Table 1 states for PM1: Do not use; considered as a component of bioinformatic analysis (PP3/BP4).
  • The VCEP defines the BRCA2 DNA binding domain as aa 2481-3186; the variant consequence starts at p.Thr2703, within that interval.
  • vcep_materials.json has domain_tables: {}, so no separate authoritative domain-table entry was available; the governing VCEP text was checked directly.
  • The three requested variant notations were searched in the four governing VCEP full-text files; no exact variant entry was found.
Still missing
  • No exact c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in Specifications_V1.2_2024-11-18.docx.
  • No exact c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in Appendices_V1.2_2024-11-18.docx.
  • No exact c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.
  • No exact c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.
Sources
vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗cspec ↗
PM2 N/ANot applicable: the VCEP excludes insertion-type indels from PM2, and c.8107dup is a frameshift duplication. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 v1.2 PM2 rule is Supporting-only and explicitly excludes insertion, deletion, and delins variants. NM_000059.4:c.8107dup is a duplication causing a frameshift, i.e. an insertion-type indel, so PM2 is not applicable under the VCEP's stated exclusion rather than being inferred from generic population absence.

VCEP rule
Absent/rare from controls in an ethnically-matched cohort population sample. ... Absent from gnomAD (exome and genome). ... 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. Do not apply if read depth <25 at region around the variant. Exclude data if variant failed quality control filter.
Evidence considered
  • Prefetch normalization identifies NM_000059.4:c.8107dup as a duplication with consequence class frameshift and protein consequence NP_000050.3:p.(Thr2703AsnfsTer3).
  • ENIGMA BRCA2 Specifications v1.2, PM2: PM2_Supporting uses gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, but the rule states not to apply it for insertion, deletion, or delins variants.
  • The population evidence reports absence from GNOMAD_V2_1_NON_CANCER and GNOMAD_V3_1_NON_CANCER, but that absence does not override the VCEP's PM2 variant-type exclusion.
Still missing
  • No variant-specific entry was found after searching SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, and HUMU-40-1557-s001.xlsx.txt for c.8107dup, p.Thr2703AsnfsTer3, and p.T2703Nfs*3.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗gnomad_v2 ↗
PM4 VCEPNot applicable: PM4 covers in-frame length changes or stop-loss variants, whereas c.8107dup is a frameshift with a premature termination codon. Details ▾Hide ▴
Reasoning

PM4 is not applicable under the ENIGMA BRCA2 specification. The criterion is limited to protein-length changes from in-frame deletions or insertions in non-repeat regions or stop-loss variants, whereas this variant is a frameshift with a premature termination codon. The VCEP explicitly says not to use PM4 and treats the relevant computational/domain analysis separately.

VCEP rule
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. ... Do not use
Evidence considered
  • ENIGMA Specifications v1.2, PM4 row: the rule is protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants; the specification states 'Do not use'.
  • Variant consequence is frameshift with a premature termination codon, not an in-frame insertion/deletion or stop-loss variant.
  • The three requested variant notations were searched in all four named governing full-text files; no variant-specific entry was found.
Still missing
  • No variant-specific entry for c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 was found in Specifications_V1.2_2024-11-18.docx.
  • No variant-specific entry for c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 was found in Appendices_V1.2_2024-11-18.docx.
  • No variant-specific entry for c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 was found in Specifications_Table4_V1.2_2024-11-18.xlsx.
  • No variant-specific entry for c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
PM6 VCEPNot applicable: the VCEP says de novo occurrences lack calibrated predictive capacity for BRCA1/2-related cancers and explicitly says not to use PM6. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP explicitly designates PM6 as not applicable and states that BRCA1/2-related cancers occur relatively commonly, with no information to calibrate the predictive capacity of de novo occurrences. Therefore, PM6 is not used even for a confirmed de novo observation without maternity and paternity confirmation.

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
  • ENIGMA BRCA2 Specification v1.2, Table 1/criterion entry for PM6: PM6 is marked Do not use because BRCA1/2-related cancers occur relatively commonly and no information calibrates the predictive capacity of de novo occurrences.
Still missing
  • No PM6 assessment is permitted under the ENIGMA BRCA2 VCEP specification.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
PP2 VCEPNot applicable: ENIGMA says not to use PP2, and this variant is a frameshift rather than a missense change. Details ▾Hide ▴
Reasoning

PP2 is not applicable because the ENIGMA BRCA2 specification explicitly says Do not use PP2 and gives the reason as a high frequency of benign missense variants. The present 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
  • ENIGMA Specifications v1.2 Table 1 states for PP2: Do not use; rationale: High frequency of benign missense variants.
  • Variant normalization identifies this as a frameshift, not a missense variant.
  • The three requested variant notations were searched in the four governing VCEP full-text files; no exact variant entry was found.
Still missing
  • No exact c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in Specifications_V1.2_2024-11-18.docx.
  • No exact c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in Appendices_V1.2_2024-11-18.docx.
  • No exact c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.
  • No exact c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.
Sources
vcep_specifications_v1_2_2024_11_18 ↗cspec ↗
PP3 N/ANot applicable: PP3 covers missense, in-frame, silent, or qualifying intronic variants, whereas c.8107dup is a frameshift. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 rule limits PP3 to missense or in-frame insertion/deletion/delins variants for protein-impact prediction, and to silent, missense/in-frame, or intronic variants outside the canonical donor/acceptor ±1,2 positions for splice prediction. This variant is NM_000059.4:c.8107dup, a frameshift producing p.(Thr2703AsnfsTer3), so it is outside PP3 scope. The recorded SpliceAI maximum delta score of 0.045 was therefore not used for PP3, and no BayesDel score is required. The specification also states not to apply PP3 if PVS1 is met at any strength.

VCEP rule
Do not apply PP3 if PVS1 is met at any strength. ... 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
  • Variant normalization identifies NM_000059.4:c.8107dup as a frameshift, NP_000050.3:p.(Thr2703AsnfsTer3), also p.(T2703Nfs*3).
  • The ENIGMA specification's PP3 scope names missense/in-frame protein-impact paths and silent, missense/in-frame, or qualifying intronic splice-prediction paths; frameshift variants are not included.
  • SpliceAI was available with DS_AG 0.005, DS_AL 0.006, DS_DG 0.000, DS_DL 0.045, maximum delta 0.045; this predictor result was not applied because the variant is outside PP3 scope.
Still missing
  • No c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗spliceai ↗
PP5 VCEPNot applicable: the ENIGMA BRCA2 specification explicitly says PP5 is not for use, and no ClinVar record was found for this variant. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP explicitly excludes PP5 from use. No ClinVar record or other qualifying independent pathogenic report was identified for this variant, but the criterion is not applicable under the governing VCEP specification.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • The ENIGMA BRCA2 CSPEC entry marks PP5 as not applicable for this VCEP.
  • The case ClinVar search returned no result for BRCA2 c.8107dup.
Sources
cspec ↗
BP1 N/ANot applicable: BP1 covers silent, missense, or in-frame variants outside domains, whereas c.8107dup is a frameshift. Details ▾Hide ▴
Reasoning

BP1 is not applicable because the ENIGMA rule applies to silent, missense, or in-frame insertion/deletion/delins variants outside a clinically important functional domain with no predicted splicing. NM_000059.4:c.8107dup is a frameshift, which is outside the variant types named by the rule; therefore the BP1 path cannot be applied.

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).
Evidence considered
  • ENIGMA Specifications v1.2 BP1 rule limits BP1_Strong to silent substitution, missense, or in-frame insertion/deletion/delins variants outside a clinically important functional domain with no predicted splicing.
  • Variant normalization identifies NM_000059.4:c.8107dup as a frameshift, so it is outside the BP1 variant classes.
  • The three requested variant notations were searched in the four governing VCEP full-text files; no exact variant entry was found.
Still missing
  • No exact c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in Specifications_V1.2_2024-11-18.docx.
  • No exact c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in Appendices_V1.2_2024-11-18.docx.
  • No exact c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.
  • No exact c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.
Sources
vcep_specifications_v1_2_2024_11_18 ↗cspec ↗
BP2 VCEPNot applicable: the ENIGMA BRCA2 specification says BP2 is not used and is applied only in the context of BS2. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 specification explicitly states that BP2 is not to be used and is applied only in the context of BS2; therefore BP2 is not applicable under this VCEP framework regardless of whether a cis or trans observation is available.

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
  • Specifications_V1.2_2024-11-18.docx, BP2 entry: observed in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with a pathogenic variant in any inheritance pattern; the VCEP disposition is 'Do not use' and 'Applied only in the context of BS2.'
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
BP3 VCEPNot applicable: BP3 covers in-frame changes in nonfunctional repetitive regions, whereas c.8107dup is a protein-truncating frameshift. Details ▾Hide ▴
Reasoning

BP3 is not applicable under the ENIGMA BRCA2 specification. The criterion is limited to in-frame deletions or insertions in a repetitive region without known function, whereas this variant is a frameshift with a premature termination codon. The VCEP explicitly says not to use BP3 and states that the relevant category is captured by bioinformatic prediction and domain analysis.

VCEP rule
In-frame deletions/insertions in a repetitive region without a known function ... Do not use
Evidence considered
  • ENIGMA Specifications v1.2, BP3 row: the rule is in-frame deletions/insertions in a repetitive region without a known function; the specification states 'Do not use' and directs capture by bioinformatic prediction and domain analysis.
  • Variant consequence is frameshift with a premature termination codon, not an in-frame deletion or insertion.
  • The three requested variant notations were searched in all four named governing full-text files; no variant-specific entry was found.
Still missing
  • No variant-specific entry for c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 was found in Specifications_V1.2_2024-11-18.docx.
  • No variant-specific entry for c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 was found in Appendices_V1.2_2024-11-18.docx.
  • No variant-specific entry for c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 was found in Specifications_Table4_V1.2_2024-11-18.xlsx.
  • No variant-specific entry for c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
BP4 N/ANot applicable: BP4 covers missense, in-frame, silent, or qualifying intronic variants, whereas c.8107dup is a frameshift. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 rule limits BP4 to missense or in-frame insertion/deletion/delins variants inside a clinically important domain, silent variants inside such a domain, or intronic variants outside donor/acceptor ±1,2 positions. This variant is NM_000059.4:c.8107dup, a frameshift producing p.(Thr2703AsnfsTer3), so it is outside BP4 scope. The recorded SpliceAI maximum delta score of 0.045 and the absence of a BayesDel score cannot establish BP4 for this variant.

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
  • Variant normalization identifies NM_000059.4:c.8107dup as a frameshift, NP_000050.3:p.(Thr2703AsnfsTer3), also p.(T2703Nfs*3).
  • The ENIGMA specification's BP4 scope names missense/in-frame, silent, and qualifying intronic variants; frameshift variants are not included.
  • SpliceAI was available with maximum delta 0.045, below the VCEP's ≤0.1 no-impact threshold, but the score was not used because the variant is outside BP4 scope; no BayesDel score was available.
Still missing
  • No c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗spliceai ↗
BP6 VCEPNot applicable: the ENIGMA BRCA2 specification explicitly says BP6 is not for use, and no ClinVar record was found for this variant. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP explicitly excludes BP6 from use. No ClinVar record or other qualifying independent benign report was identified for this variant, but the criterion is not applicable under the governing VCEP specification.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • The ENIGMA BRCA2 CSPEC entry marks BP6 as not applicable for this VCEP.
  • The case ClinVar search returned no result for BRCA2 c.8107dup.
Sources
cspec ↗
BP7 N/ANot applicable: BP7 covers silent, intronic, or missense/in-frame variants, whereas c.8107dup is a frameshift. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 rule limits BP7 to silent variants inside a clinically important domain when BP4 is met, or intronic variants at or beyond +7/-21 positions when BP4 is met. Its repurposed BP7_Strong (RNA) path covers intronic, silent, and missense/in-frame variants outside a clinically important domain. This variant is a frameshift, so it is outside all BP7 paths. The SpliceAI maximum delta score of 0.045 was not used to assign 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. ... Apply as BP7_Strong (RNA) for intronic, silent, and missense/in-frame variants located outside a (potentially) clinically important functional domain.
Evidence considered
  • Variant normalization identifies NM_000059.4:c.8107dup as a frameshift, NP_000050.3:p.(Thr2703AsnfsTer3), also p.(T2703Nfs*3).
  • The ENIGMA specification's BP7 paths name silent, intronic, and missense/in-frame variants, and require BP4 for the basic silent/intronic paths; frameshift variants are not included.
  • SpliceAI was available with maximum delta 0.045, but it was not used because the variant is outside BP7 scope.
Still missing
  • No c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗spliceai ↗

Identifiers

Gene
BRCA2
Transcript
NM_000059.4
Coding (HGVS c.)
NM_000059.4:c.8107dup
Protein (HGVS p.)
NP_000050.3:p.(Thr2703AsnfsTer3)
GRCh38
chr13:32363306 G>GA
GRCh37
chr13:32937443 G>GA
Location and type
Exon 18 · frameshift

Gene diagram

Every interpreted variant in BRCA2, mapped onto the exon structure of NM_000059.4. Select a row to find it on the plot.

BRCA2NM_000059.4
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -127 bp
0.006
SpliceAI acceptor gainat +64 bp
0.005
SpliceAI donor lossat +227 bp
0.045
SpliceAI donor gainat -82 bp
0.000
Pangolin splice lossmagnitude shown
-0.068
Pangolin splice gain
0.014

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 N/ANot applicable: PP3 covers missense, in-frame, silent, or qualifying intronic variants, whereas c.8107dup is a frameshift. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 rule limits PP3 to missense or in-frame insertion/deletion/delins variants for protein-impact prediction, and to silent, missense/in-frame, or intronic variants outside the canonical donor/acceptor ±1,2 positions for splice prediction. This variant is NM_000059.4:c.8107dup, a frameshift producing p.(Thr2703AsnfsTer3), so it is outside PP3 scope. The recorded SpliceAI maximum delta score of 0.045 was therefore not used for PP3, and no BayesDel score is required. The specification also states not to apply PP3 if PVS1 is met at any strength.

VCEP rule
Do not apply PP3 if PVS1 is met at any strength. ... 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
  • Variant normalization identifies NM_000059.4:c.8107dup as a frameshift, NP_000050.3:p.(Thr2703AsnfsTer3), also p.(T2703Nfs*3).
  • The ENIGMA specification's PP3 scope names missense/in-frame protein-impact paths and silent, missense/in-frame, or qualifying intronic splice-prediction paths; frameshift variants are not included.
  • SpliceAI was available with DS_AG 0.005, DS_AL 0.006, DS_DG 0.000, DS_DL 0.045, maximum delta 0.045; this predictor result was not applied because the variant is outside PP3 scope.
Still missing
  • No c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗spliceai ↗
BP4 N/ANot applicable: BP4 covers missense, in-frame, silent, or qualifying intronic variants, whereas c.8107dup is a frameshift. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 rule limits BP4 to missense or in-frame insertion/deletion/delins variants inside a clinically important domain, silent variants inside such a domain, or intronic variants outside donor/acceptor ±1,2 positions. This variant is NM_000059.4:c.8107dup, a frameshift producing p.(Thr2703AsnfsTer3), so it is outside BP4 scope. The recorded SpliceAI maximum delta score of 0.045 and the absence of a BayesDel score cannot establish BP4 for this variant.

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
  • Variant normalization identifies NM_000059.4:c.8107dup as a frameshift, NP_000050.3:p.(Thr2703AsnfsTer3), also p.(T2703Nfs*3).
  • The ENIGMA specification's BP4 scope names missense/in-frame, silent, and qualifying intronic variants; frameshift variants are not included.
  • SpliceAI was available with maximum delta 0.045, below the VCEP's ≤0.1 no-impact threshold, but the score was not used because the variant is outside BP4 scope; no BayesDel score was available.
Still missing
  • No c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗spliceai ↗
BP7 N/ANot applicable: BP7 covers silent, intronic, or missense/in-frame variants, whereas c.8107dup is a frameshift. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 rule limits BP7 to silent variants inside a clinically important domain when BP4 is met, or intronic variants at or beyond +7/-21 positions when BP4 is met. Its repurposed BP7_Strong (RNA) path covers intronic, silent, and missense/in-frame variants outside a clinically important domain. This variant is a frameshift, so it is outside all BP7 paths. The SpliceAI maximum delta score of 0.045 was not used to assign 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. ... Apply as BP7_Strong (RNA) for intronic, silent, and missense/in-frame variants located outside a (potentially) clinically important functional domain.
Evidence considered
  • Variant normalization identifies NM_000059.4:c.8107dup as a frameshift, NP_000050.3:p.(Thr2703AsnfsTer3), also p.(T2703Nfs*3).
  • The ENIGMA specification's BP7 paths name silent, intronic, and missense/in-frame variants, and require BP4 for the basic silent/intronic paths; frameshift variants are not included.
  • SpliceAI was available with maximum delta 0.045, but it was not used because the variant is outside BP7 scope.
Still missing
  • No c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No c.8107dup, p.Thr2703AsnfsTer3, or p.T2703Nfs*3 entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).

5 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Truncated BRCA2 is cytoplasmic: implications for cancer-linked mutations.
    The paper does not mention BRCA2 c.8107dup or p.(T2703Nfs*3); it reports C-terminal localization experiments for other BRCA2 truncations and contains no variant-specific segregation analysis.
    Does not name this variant
    PMID 10570174 ↗
    Quoted passage
    In summary, within the final 156 amino acids of BRCA2 reside NLS1 and NLS3, the two functional NLSs of BRCA2.

    Results, paragraph beginning "BRCA2 NLSs Reside in the Extreme C Terminus"

  • BRCA2 is required for homology-directed repair of chromosomal breaks.
    The paper does not mention BRCA2 c.8107dup or p.(T2703Nfs*3); it reports homology-directed repair assays for other BRCA2 mutations and contains no variant-specific segregation analysis.
    Does not name this variant
    PMID 11239455 ↗
    Quoted passage
    We find that BRCA2 mutant cell lines are recombination deficient, such that homology-directed repair is reduced 6- to .100-fold, depending on the cell line.

    Summary; Results sections on BRCA2-deficient CAPAN-1 and Brca2-deficient ES cells

  • A new mutation of BRCA2 gene in an Italian healthy woman with familial breast cancer history.
    The paper does not mention BRCA2 c.8107dup or p.(T2703Nfs*3); it describes a different BRCA2 insertion in three family members and is not evidence for segregation of the case variant.
    Does not name this variant
    PMID 20878484 ↗
    Quoted passage
    In this study, we have identified in a Italian healthy woman a pathological mutation in exon 15, the 7525_7526insT [in reference to coding sequence, NP_000050.2; 7753insT in reference to complete mRNA NM_000059.3], that causes a frame shift [p.Ser2509fs], resulting in a stop codon 29 amino acids downstream.

    Results, first paragraph

  • BRCA1 and BRCA2: different roles in a common pathway of genome protection.
    The paper does not mention BRCA2 c.8107dup or p.(T2703Nfs*3); it discusses BRCA2 gene-level homologous-recombination biology and contains no variant-specific segregation analysis.
    Does not name this variant
    PMID 22193408 ↗
    Quoted passage
    In contrast to the multifunctional activities of BRCA1, the primary function of BRCA2 is in HR.

    Section: "BRCA2 functional domains and binding partners"

  • A comprehensive focus on global spectrum of BRCA1 and BRCA2 mutations in breast cancer.
    The paper does not mention BRCA2 c.8107dup or p.(T2703Nfs*3); it is a gene-level review of BRCA2 mutations and contains no variant-specific segregation analysis.
    Does not name this variant
    PMID 24312913 ↗
    Quoted passage
    In BRCA2 gene, most of mutations occur in exons 10 and 11 and usually include insertions or deletions which raise the missense alterations and premature stop codon ending in truncated and nonfunctional protein.

    Section 3, "BRCA1 and BRCA2 Mutations"

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.045 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).

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 not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.