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BRCA2c.7908T>APathogenic
Print report
Variant interpretation report

BRCA2 c.7908T>A, p.(Cys2636Ter)

NM_000059.4:c.7908T>A NP_000050.3:p.(Cys2636Ter) Nonsense · exon 17 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: 3 Benign evidence criteria: 0
Pathogenic criteria applied · 3
PVS1Very strong
PVS1 · very strong

Met, very strong: ENIGMA Table 4 assigns PVS1 to BRCA2 exon 17 PTCs, and p.Cys2636Ter truncates 783 of 3418 amino acids upstream of the terminal exon.

PM5Strong
PM5 · strong

Met, Strong: ENIGMA Table 4 assigns PM5_Strong (PTC) to BRCA2 exon 17, which contains c.7908.

PP5Supporting
PP5 · supporting

Met, Supporting: exact ClinVar variation 52433 has an ENIGMA expert-panel Pathogenic classification, satisfying the requested PP5 rule.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Pathogenic

Pathogenic: ENIGMA Table 3's one Very Strong plus one Strong rule is met by PVS1 (very strong) and PM5 (strong, PTC).

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
0.023 maximum delta

Recorded SpliceAI maximum delta score: 0.023. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
4 reported laboratory submissions

4 Pathogenic. ClinVar API review status: reviewed by expert panel.

Applied · PP5 → 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: 3 met · 3 not met · 10 not assessed · 12 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

The consequence-specific assessment supports full-strength ENIGMA PVS1 for the exon 17 nonsense PTC; PM4 and BP3 are not applicable to this variant type under the governing framework.

For the requested codon/residue/domain criteria, only PM5 applies: ENIGMA Table 4 pre-assigns PM5_Strong (PTC) for BRCA2 exon 17, which contains c.7908.

PS1, PM1, PP2, and BP1 are not applicable because the variant is a nonsense PTC and the governing ENIGMA rules restrict those criteria to different variant classes or evidence types.

Population evidence is not benign: the variant is absent from the governing non-cancer gnomAD datasets, excluding BA1 and BS1 frequency thresholds.

PM2 cannot be applied without the ENIGMA-required regional average read-depth verification, and BS2 lacks phenotype-qualified individual observations.

The three on-record VCEP full-text files were searched for c.7908T>A, p.Cys2636Ter, and p.C2636*; no variant-specific pre-assigned population code was found.

Met · 3

PVS1 Very strongMet, very strong: ENIGMA Table 4 assigns PVS1 to BRCA2 exon 17 PTCs, and p.Cys2636Ter truncates 783 of 3418 amino acids upstream of the terminal exon. Details ▾Hide ▴
Reasoning

NM_000059.4:c.7908T>A is a nonsense variant, p.(Cys2636Ter)/p.(C2636*), in BRCA2 exon 17, whose coding interval is c.7806-c.7976. The ENIGMA BRCA2 Table 4 assigns PVS1 to the exon 17 PTC category and the specification states that BRCA2 loss of function is an established disease mechanism. The predicted product terminates at amino acid 2636 instead of the 3418-residue reference protein, a 783-residue truncation; because exon 17 is well upstream of the terminal exon and the stop is not in the terminal coding region, the transcript is expected to undergo nonsense-mediated decay rather than escape NMD. No VCEP downgrade rule for exon 17 PTCs applies. The exact variant notation was not present as a variant-level row in the governing files, but the governing exon-level PTC row is applicable.

Rule
ENIGMA BRCA2 V1.2 Table 4: exon 17 PTC = PVS1; full-strength PVS1 is reported as very strong.
Evidence considered
  • The case normalization identifies NM_000059.4:c.7908T>A as NP_000050.3:p.(Cys2636Ter)/p.(C2636*), a nonsense change, with the predicted protein ending at residue 2636 while the reference ends at residue 3418.
  • Specifications Table 4 lists BRCA2 exon 17, coding interval c.7806-c.7976, PTC code PVS1, and exon 17 protein interval p.2602-p.2659; c.7908 lies within this exon.
  • The ENIGMA specification defines PVS1_VariableWeight for null variants in genes where loss of function is a known disease mechanism and directs PTC variants to the exon-specific Table 4 decision tree.
  • The stop is in exon 17 of 27 and therefore is far upstream of the terminal coding exon; the 783-residue truncation is not a terminal-exon NMD-escape situation.
Still missing
  • No exact c.7908T>A, p.Cys2636Ter, or p.C2636* entry was found in Specifications_V1.2_2024-11-18.docx.txt; its exon-level PVS1 rule was used.
  • No exact c.7908T>A, p.Cys2636Ter, or p.C2636* entry was found in Appendices_V1.2_2024-11-18.docx.txt; its PVS1 framework was used.
  • No exact c.7908T>A, p.Cys2636Ter, or p.C2636* entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt; its BRCA2 E17 PTC row was used.
  • No exact c.7908T>A, p.Cys2636Ter, or p.C2636* entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt; no variant-specific splice evidence was available from that paper.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_specifications_table4_v1_2_2024_11_18
PM5 StrongMet, Strong: ENIGMA Table 4 assigns PM5_Strong (PTC) to BRCA2 exon 17, which contains c.7908. Details ▾Hide ▴
Reasoning

PM5 is met at Strong strength as PM5_Strong (PTC). The variant is a nonsense protein-termination change in BRCA2 exon 17: c.7908 lies within the exon 17 coding interval c.7806-c.7976, and the governing ENIGMA Table 4 assigns PM5_Strong (PTC) to BRCA2 exon 17. The specification states that PM5(PTC) is exon-specific additional weight for PTC variants that meet PVS1; it is not classic same-residue missense PM5. The variant's exact notations were not listed as rows in the searched VCEP text, but the pre-assigned exon-level rule governs this case.

Rule
Apply the exon-specific PM5(PTC) code to PVS1-eligible protein-termination variants; BRCA2 exon 17 is assigned PM5_Strong (PTC).
Evidence considered
  • Specifications_Table4_V1.2_2024-11-18.xlsx.txt lists BRCA2 exon 17 as c.7806-c.7976 and assigns PVS1 for coding PTC variants plus PM5_Strong (PTC).
  • c.7908 falls within the exon 17 coding interval, and the case normalization identifies the consequence as nonsense with p.Cys2636Ter.
  • The ENIGMA Appendix D rule states that PM5(PTC) is exon-specific, applies to nonsense and frameshift changes meeting PVS1, and is distinct from classic same-residue missense PM5.
Still missing
  • No exact c.7908T>A, p.Cys2636Ter, or p.C2636* entry was found in Specifications_V1.2_2024-11-18.docx.txt; the exon-level PM5(PTC) rule is nevertheless explicit.
  • No exact c.7908T>A, p.Cys2636Ter, or p.C2636* entry was found in Appendices_V1.2_2024-11-18.docx.txt; the exon-level PM5(PTC) rule is nevertheless explicit.
  • No exact c.7908T>A, p.Cys2636Ter, or p.C2636* entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt; Table 4 assigns the governing code by exon rather than by an exact variant row.
Sources
vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_specifications_table4_v1_2_2024_11_18
PP5 SupportingMet, Supporting: exact ClinVar variation 52433 has an ENIGMA expert-panel Pathogenic classification, satisfying the requested PP5 rule. Details ▾Hide ▴
Reasoning

Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Pathogenic.

Rule
Exact-variant ClinVar expert-panel Pathogenic/Likely Pathogenic classification supports PP5 at Supporting strength under the requested global rule.
Evidence considered
  • ClinVar variation 52433 exactly matches NM_000059.4(BRCA2):c.7908T>A (p.Cys2636Ter).
  • ClinVar reports Pathogenic with review status reviewed by expert panel and three review stars; the expert panel is ENIGMA.
  • Ordinary laboratory submissions and aggregate labels were not used to trigger PP5; only the exact-variant expert-panel assertion was used.
  • The ENIGMA specification says PP5 is not applicable, but the requested global criterion rule requires exact ClinVar expert-panel Pathogenic/Likely Pathogenic classifications to support PP5.
  • ClinVar expert panel classification
Sources
clinvar ↗cspec ↗

Not met · 3 · evaluated, threshold not reached

BA1 Not met: the variant is absent from the governing non-cancer gnomAD datasets, so no filter allele frequency exceeds the ENIGMA BA1 threshold of 0.1%. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA2 specification defines BA1 as filter allele frequency above 0.001 (0.1%) in a non-founder population, using gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes, with read depth at least 20 and no failed quality-control filter. The case evidence reports the variant absent from gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer, so no allele frequency meeting the BA1 threshold is present. The governing specification's direct variant tables and the supplied HUMU-40-1557-s001 table were searched for c.7908T>A, p.Cys2636Ter, and p.C2636*; no variant-specific pre-assigned BA1 entry was found.

Rule
Filter allele frequency (FAF) is above 0.1% (FAF > 0.001) in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes, in a non-founder population; do not apply if read depth is <20 or quality control failed.
Evidence considered
  • ENIGMA BRCA2 v1.2 defines BA1 as filter allele frequency above 0.001 (0.1%) in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes, with read depth at least 20 and quality-control exclusions.
  • The case gnomAD results report c.7908T>A absent from gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer; therefore no observed frequency reaches 0.001.
  • The on-record Specifications, Appendices, and HUMU-40-1557-s001 full-text files were searched under c.7908T>A, p.Cys2636Ter, and p.C2636*; none contains a variant-specific BA1 assignment.
Still missing
  • The case data do not provide a numeric read-depth or quality-control value for the absent gnomAD records; therefore the dataset-level depth/QC audit trail is unavailable, although absence precludes a frequency above 0.1%.
  • No entry for c.7908T>A, p.Cys2636Ter, or p.C2636* was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.7908T>A, p.Cys2636Ter, or p.C2636* was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No entry for c.7908T>A, p.Cys2636Ter, or p.C2636* was found in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_humu_40_1557_s001
BS1 Not met: the variant is absent from both governing non-cancer gnomAD datasets, so its frequency does not reach the ENIGMA BS1 threshold of 0.01%. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA2 specification defines BS1 as filter allele frequency above 0.0001 (0.01%) for strong BS1, or above 0.00002 (0.002%) through 0.0001 for BS1_Supporting, in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes, with read depth at least 20 and no failed quality-control filter. The case evidence reports the variant absent from both governing non-cancer datasets, so no allele frequency reaches either BS1 interval. No variant-specific pre-assigned BS1 entry was found in the searched governing VCEP files.

Rule
Apply BS1 for FAF above 0.0001 (0.01%), or BS1_Supporting for FAF >0.00002 (0.002%) and <=0.0001, in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes, with read depth at least 20 and no failed quality-control filter.
Evidence considered
  • ENIGMA BRCA2 v1.2 defines BS1 as FAF >0.0001 for strong evidence and >0.00002 to <=0.0001 for supporting evidence in non-cancer gnomAD v2.1 exomes and/or v3.1 genomes, subject to depth and QC requirements.
  • The case gnomAD results report c.7908T>A absent from gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer; therefore no observed frequency reaches the BS1 range.
  • The on-record Specifications, Appendices, and HUMU-40-1557-s001 full-text files were searched under c.7908T>A, p.Cys2636Ter, and p.C2636*; none contains a variant-specific BS1 assignment.
Still missing
  • The case data do not provide a numeric read-depth or quality-control value for the absent gnomAD records; therefore the dataset-level depth/QC audit trail is unavailable.
  • No entry for c.7908T>A, p.Cys2636Ter, or p.C2636* was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.7908T>A, p.Cys2636Ter, or p.C2636* was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No entry for c.7908T>A, p.Cys2636Ter, or p.C2636* was found in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_humu_40_1557_s001
BP6 Not met: exact ClinVar variation 52433 is Pathogenic by an ENIGMA expert panel, not Benign or Likely Benign for BP6. Details ▾Hide ▴
Reasoning

The exact ClinVar record for NM_000059.4:c.7908T>A (p.Cys2636Ter) has an ENIGMA expert-panel Pathogenic classification, not Benign or Likely Benign. No exact-variant ClinVar expert-panel benign assertion is present, so the requested BP6 trigger is not met. The ordinary laboratory Pathogenic submissions and aggregate label were not used for the decision.

Rule
Exact-variant ClinVar expert-panel Benign/Likely Benign classification supports BP6 at Supporting strength under the requested global rule.
Evidence considered
  • ClinVar variation 52433 exactly matches the assessed transcript and protein change.
  • The expert-panel classification is Pathogenic, with ENIGMA identified as the expert panel.
  • No exact-variant ClinVar expert-panel Benign or Likely Benign classification was identified; ordinary laboratory submissions and aggregate labels were not used.
Sources
clinvar ↗cspec ↗

Not assessed · 10 · no assessment recorded

PS3 Not assessed: no calibrated damaging functional-assay result was found for c.7908T>A, p.Cys2636Ter, or p.C2636*. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 Version 1.2 framework requires well-established functional studies showing a damaging effect and directs reviewers to calibrated assay recommendations in Specifications Table 9. The exact variant was not found in Specifications_Table9_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 under c.7908T>A, p.Cys2636Ter, or p.C2636*. The available extracted literature reports functional findings for other BRCA2 variants or gene-level biology, not this variant, so a calibrated PS3 strength cannot be assigned.

Rule
ENIGMA PS3: well-established in vitro or in vivo functional studies supportive of a damaging effect; apply for assays measuring protein function, or mRNA and protein combined. Use calibrated recommendations in Specifications Table 9.
Evidence considered
  • ENIGMA BRCA1/2 Version 1.2 states that PS3 applies to well-established in vitro or in vivo functional studies showing a damaging effect and refers to calibrated published assay recommendations in Table 9.
  • The full converted Table 9 text contains no row for c.7908T>A, p.Cys2636Ter, or p.C2636*.
  • The reviewed paper extracts for PMID:10570174, PMID:11239455, PMID:20104584, PMID:20878484, PMID:22193408, and PMID:24312913 explicitly state that the exact variant was not mentioned or tested; their findings concern other variants or gene-level biology.
Still missing
  • No exact-variant entry found in Specifications_Table9_V1.2_2024-11-18.xlsx after searching c.7908T>A, p.Cys2636Ter, and p.C2636*.
  • No exact-variant entry found in Specifications_V1.2_2024-11-18.docx after searching c.7908T>A, p.Cys2636Ter, and p.C2636*.
  • No exact-variant entry found in Appendices_V1.2_2024-11-18.docx after searching c.7908T>A, p.Cys2636Ter, and p.C2636*.
  • No exact-variant entry found in HUMU-40-1557-s001.xlsx after searching c.7908T>A, p.Cys2636Ter, and p.C2636*.
  • No validated variant-specific protein-function assay result is available in the reviewed case evidence.
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_humu_40_1557_s001PMID:10570174 ↗PMID:11239455 ↗PMID:20104584 ↗PMID:20878484 ↗PMID:22193408 ↗PMID:24312913 ↗
PS4 Not assessed: no variant-specific case-control OR, confidence interval, p-value, or qualifying affected/control counts were available for the PS4 OR >=4 threshold. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 specification defines PS4 Strong as case-control evidence with p-value <=0.05 and OR >=4, with the lower confidence interval excluding 2.0. No case-control odds ratio, confidence interval, p-value, or qualifying affected/control counts were available for NM_000059.4:c.7908T>A (p.Cys2636Ter; p.C2636*). The exact variant was not found in HUMU-40-1557-s001.xlsx or the searchable text of Specifications_V1.2_2024-11-18.docx; the declared SupplementaryTables_V1.2.xlsx full text is unavailable for authoritative lookup. The ClinVar expert-panel Pathogenic classification is not case-control enrichment and cannot independently establish PS4.

Rule
Case-control studies; p-value <=0.05 and OR >=4, with lower confidence interval excluding 2.0.
Evidence considered
  • ENIGMA BRCA2 Specifications v1.2 states: "Case-control studies; p-value <=0.05 and OR >=4 (lower confidence interval excludes 2.0)."
  • The exact variant was searched as c.7908T>A, p.Cys2636Ter, and p.C2636* in the governing searchable VCEP files; no entry was found in HUMU-40-1557-s001.xlsx or Specifications_V1.2-2024-11-18.docx.txt.
  • The VCEP index declares SupplementaryTables_V1.2.xlsx as a PS4 source but its full text is unavailable, so its ST7 lookup cannot be confirmed.
  • ClinVar expert-panel Pathogenic classification is classification evidence, not a PS4 case-control estimate.
Still missing
  • No exact-variant entry for c.7908T>A, p.Cys2636Ter, or p.C2636* was found in HUMU-40-1557-s001.xlsx.
  • No exact-variant entry for c.7908T>A, p.Cys2636Ter, or p.C2636* was found in Specifications_V1.2_2024-11-18.docx.txt.
  • SupplementaryTables_V1.2.xlsx full text is unavailable for authoritative ST7 lookup, as declared by the VCEP index.
Sources
cspec ↗vcep_humu_40_1557_s001vcep_supplementarytables_v1_2_2024_11_18
PM2 Not assessed: the variant is absent from both required non-cancer gnomAD datasets, but the ENIGMA PM2 prerequisite of regional average read depth at least 25 is undocumented. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA2 specification defines PM2_Supporting as absence from controls in gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, with the region around the variant having average read depth at least 25. The case evidence reports c.7908T>A absent from both non-cancer datasets, but supplies no numeric regional read-depth value and no quality-control/depth record. Because the specified depth prerequisite cannot be verified, PM2_Supporting is not assessed rather than applied. No variant-specific pre-assigned PM2 entry was found in the searched governing VCEP files.

Rule
PM2_Supporting requires absence from gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, with regional average read depth >=25.
Evidence considered
  • ENIGMA BRCA2 v1.2 defines PM2_Supporting as absence from gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, with regional average read depth at least 25.
  • The case gnomAD results report c.7908T>A absent from gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer, but provide no regional depth value or callable-region QC record.
  • The on-record Specifications, Appendices, and HUMU-40-1557-s001 full-text files were searched under c.7908T>A, p.Cys2636Ter, and p.C2636*; none contains a variant-specific PM2 assignment.
Still missing
  • Regional average read depth for c.7908T>A is not provided for gnomAD v2.1 non-cancer exomes or gnomAD v3.1 non-cancer genomes.
  • The case data do not provide a numeric quality-control status or callable-region audit for the absent records.
  • No entry for c.7908T>A, p.Cys2636Ter, or p.C2636* was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.7908T>A, p.Cys2636Ter, or p.C2636* was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No entry for c.7908T>A, p.Cys2636Ter, or p.C2636* was found in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_humu_40_1557_s001
PM3 Not assessed: no Fanconi Anemia phenotype, same-gene pathogenic co-variant, or verified phase is documented for PM3 application. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 Specification V1.2 governs PM3 and restricts it to BRCA1/2-related Fanconi Anemia cases with a co-occurrent pathogenic or likely pathogenic variant in the same gene. The available case evidence documents the target BRCA2 nonsense variant but provides no affected-proband Fanconi Anemia phenotype, chromosome-breakage result, second BRCA2 pathogenic/likely pathogenic variant, or verified phase information; therefore the required PM3 evidence cannot be assessed. The target variant was not found under c.7908T>A, p.Cys2636Ter, or p.C2636* in Specifications_V1.2_2024-11-18.docx.txt.

Rule
Apply for a patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia and co-occurrent variants in the same gene; PM3_Strong = 4 or more points, PM3 = 2 points, and PM3_Supporting = 1 point.
Evidence considered
  • ENIGMA BRCA1/2 Specification V1.2 states that PM3 applies only to a patient with a phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia and a co-occurrent variant in the same gene classified as pathogenic or likely pathogenic.
  • ENIGMA Table 6 assigns PM3-related points only for pathogenic/likely pathogenic variants in trans or homozygous status, phase unknown, and a qualifying Fanconi Anemia phenotype; the available case evidence supplies none of these required observations.
  • The consolidated case-evidence bundle and remaining case JSON materials contain no documented same-gene co-occurrence, phase, or Fanconi Anemia phenotype for this variant.
Still missing
  • No affected-proband Fanconi Anemia phenotype or DEB/MMC/spontaneous chromosome-breakage result is documented.
  • No co-occurrent BRCA2 pathogenic or likely pathogenic variant is documented.
  • No parental testing, haplotype data, or other verified phase information is documented.
  • No entry for c.7908T>A, p.Cys2636Ter, or p.C2636* was found in /Users/gs_agent/LYFESCI_HERMES_v9/vcep_db/BRCA2/fulltext/Specifications_V1.2_2024-11-18.docx.txt.
Sources
cspec ↗
PP1 Not assessed: no variant-specific pedigree or quantitative segregation LR was available to compare with the PP1 threshold of LR >=2.08. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP requires quantitative co-segregation analysis for PP1 and assigns PP1 Supporting at LR >=2.08, PP1_Moderate at LR >=4.3, PP1_Strong at LR >=18.7, and PP1_Very Strong at LR >=350. No pedigree-level segregation observations, affected/unaffected tested relatives, meioses, or quantitative co-segregation LR for NM_000059.4:c.7908T>A (p.Cys2636Ter; p.C2636*) are present in the case evidence. The HUMU-40-1557-s001 converted text was searched under the coding and protein notations and contained no entry for this variant; SupplementaryTables_V1.2.xlsx full text is unavailable, so its possible ST7 lookup cannot be verified.

Rule
Apply PP1 only from quantitative co-segregation analysis: 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 VCEP v1.2 requires a quantitative co-segregation method for PP1 and defines LR thresholds of >=2.08 for supporting, >=4.3 for moderate, >=18.7 for strong, and >=350 for very strong evidence.
  • The consolidated case-evidence bundle and the directly available case files were reviewed for proband phenotype, parental testing, affected and unaffected relatives, meioses, pedigree data, and a variant-specific co-segregation likelihood ratio; none was documented for this variant.
  • HUMU-40-1557-s001.xlsx converted full text was searched under c.7908T>A, p.Cys2636Ter, and p.C2636* with no matching entry; SupplementaryTables_V1.2.xlsx could not be converted to searchable full text.
Still missing
  • No affected-relative genotypes, unaffected-relative genotypes, meioses, pedigree structure, or quantitative co-segregation LR were provided.
  • HUMU-40-1557-s001.xlsx was searched for c.7908T>A, p.Cys2636Ter, and p.C2636*; no entry was found.
  • SupplementaryTables_V1.2.xlsx full text is unavailable; the declared ST7 Reference Set lookup for this variant cannot be verified.
Sources
cspec ↗vcep_humu_40_1557_s001vcep_supplementarytables_v1_2_2024_11_18
PP4 Not assessed: the gene-specific clinical-history table has no c.7908T>A row, so no combined LR can be compared with the PP4 >=2.08 threshold. Details ▾Hide ▴
Reasoning

ENIGMA restricts PP4 to a combined multifactorial clinical likelihood ratio and states that PP4 is not applicable when the combined LR is >0.48 and <2.08; its strength thresholds are Supporting LR >=2.08, Moderate LR >=4.3, Strong LR >=18.7, and Very Strong LR >=350. The gene-specific PMID_31853058_BRCA2_clinical_history_LR.xlsx table contains no exact BRCA2 c.7908T>A row, so no variant-specific clinical-history LR can be assigned. Easton et al. is methodology/context only and provides no exact-variant LR in the supplied evidence.

Rule
Use only combined multifactorial clinical LR; PP4 Supporting >=2.08, Moderate >=4.3, Strong >=18.7, Very Strong >=350; neutral zone >0.48 and <2.08.
Evidence considered
  • ENIGMA specifies PP4 as combined multifactorial clinical data and gives Supporting LR >=2.08, Moderate LR >=4.3, Strong LR >=18.7, and Very Strong LR >=350.
  • The gene-specific clinical-history table was searched for exact Gene=BRCA2 and HGVS_Nucleotide=c.7908T>A; no row was found.
  • The VCEP index states that PMID:31853058 is the required variant-level clinical-history LR source and that PMID:17924331 is methodology/context, not a substitute for an exact variant LR.
Still missing
  • No exact BRCA2 c.7908T>A entry was found in PMID_31853058_BRCA2_clinical_history_LR.xlsx.
  • No exact-variant combined multifactorial LR was available from the supplied Easton methodology source PMID:17924331.
Sources
cspec ↗vcep_pmid_31853058_brca2_clinical_history_lrPMID:31853058 ↗PMID:17924331 ↗
BS2 Not assessed: no individual-level homozygote, healthy-carrier, age, follow-up, or Fanconi Anemia phenotype data are available to assign ENIGMA BS2 points. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA2 specification applies BS2 through phenotype-qualified observations in healthy or appropriately aged individuals, with point assignment for homozygotes, phase-known co-occurrence, or unaffected/cancer-free follow-up and final strength based on the summed points. The supplied evidence reports no homozygote observations, healthy-carrier observations, age-at-follow-up data, cancer diagnoses, Fanconi Anemia phenotype assessment, or individual-level population records for this variant. The specification explicitly states that homozygotes in gnomAD are not to be used for BS2 frequency evidence; none are reported here. No variant-specific pre-assigned BS2 entry was found in the searched governing VCEP files.

Rule
Apply BS2 only from phenotype-qualified healthy or appropriately aged individuals according to ENIGMA Table 8 point assignments; do not use gnomAD frequency observations as BS2.
Evidence considered
  • ENIGMA BRCA2 Table 8 assigns BS2 points from phenotype-qualified individuals based on genotype phase or homozygosity and age/cancer follow-up, with BS2 at 4 or more points, BS2_Moderate at 2 points, and BS2_Supporting at 1 point.
  • The case evidence contains no individual-level healthy-carrier, homozygote, age, follow-up, cancer-status, or Fanconi Anemia phenotype observation for c.7908T>A.
  • ENIGMA Appendix H states that homozygotes observed in gnomAD are frequency evidence for BA1 or BS1 and must not be repurposed as BS2; the available gnomAD records report absence rather than any homozygote count.
Still missing
  • No individual-level observations with genotype, age, cancer status, follow-up, or Fanconi Anemia phenotype are available for BS2 point assignment.
  • No entry for c.7908T>A, p.Cys2636Ter, or p.C2636* was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.7908T>A, p.Cys2636Ter, or p.C2636* was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No entry for c.7908T>A, p.Cys2636Ter, or p.C2636* was found in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_humu_40_1557_s001
BS3 Not assessed: no calibrated benign functional-assay result was found for c.7908T>A, p.Cys2636Ter, or p.C2636*. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 Version 1.2 framework requires well-established functional studies showing no damaging effect and directs reviewers to calibrated assay recommendations in Specifications Table 9; conflicting well-established assay results should not be applied. The exact variant was not found in Specifications_Table9_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 under c.7908T>A, p.Cys2636Ter, or p.C2636*. The available extracted literature reports functional findings for other BRCA2 variants or gene-level biology, not this variant, so a calibrated BS3 strength cannot be assigned.

Rule
ENIGMA BS3: well-established in vitro or in vivo functional studies showing no damaging effect on protein function; apply for assays measuring protein function, or mRNA and protein combined. Use calibrated recommendations in Specifications Table 9 and do not apply with unexplained conflicting assay results.
Evidence considered
  • ENIGMA BRCA1/2 Version 1.2 states that BS3 applies to well-established in vitro or in vivo functional studies showing no damaging effect on protein function, with calibrated recommendations in Table 9, and should not be applied when unexplained conflicting assay results exist.
  • The full converted Table 9 text contains no row for c.7908T>A, p.Cys2636Ter, or p.C2636*.
  • The reviewed paper extracts for PMID:10570174, PMID:11239455, PMID:20104584, PMID:20878484, PMID:22193408, and PMID:24312913 explicitly state that the exact variant was not mentioned or tested; their findings concern other variants or gene-level biology.
Still missing
  • No exact-variant entry found in Specifications_Table9_V1.2_2024-11-18.xlsx after searching c.7908T>A, p.Cys2636Ter, and p.C2636*.
  • No exact-variant entry found in Specifications_V1.2_2024-11-18.docx after searching c.7908T>A, p.Cys2636Ter, and p.C2636*.
  • No exact-variant entry found in Appendices_V1.2_2024-11-18.docx after searching c.7908T>A, p.Cys2636Ter, and p.C2636*.
  • No exact-variant entry found in HUMU-40-1557-s001.xlsx after searching c.7908T>A, p.Cys2636Ter, and p.C2636*.
  • No validated variant-specific protein-function assay result showing no damaging effect is available in the reviewed case evidence.
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_humu_40_1557_s001PMID:10570174 ↗PMID:11239455 ↗PMID:20104584 ↗PMID:20878484 ↗PMID:22193408 ↗PMID:24312913 ↗
BS4 Not assessed: no variant-specific non-segregation data or quantitative LR was available to compare with the BS4 supporting threshold of LR <=0.48. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP requires quantitative co-segregation analysis for BS4 and assigns BS4 Supporting at LR <=0.48, BS4_Moderate at LR <=0.23, BS4 at LR <=0.05, and BS4_Very Strong at LR <=0.00285. No variant-specific non-segregation observations, affected-relative genotypes, meioses, pedigree structure, or quantitative co-segregation LR for NM_000059.4:c.7908T>A (p.Cys2636Ter; p.C2636*) are present in the case evidence. The HUMU-40-1557-s001 converted text was searched under the coding and protein notations and contained no entry for this variant; SupplementaryTables_V1.2.xlsx full text is unavailable, so its possible ST7 lookup cannot be verified.

Rule
Apply BS4 only from quantitative co-segregation analysis: BS4_Supporting LR <=0.48:1; BS4_Moderate LR <=0.23:1; BS4 LR <=0.05:1; BS4_Very Strong LR <=0.00285:1.
Evidence considered
  • ENIGMA VCEP v1.2 requires a quantitative co-segregation method for BS4 and defines LR thresholds of <=0.48 for supporting, <=0.23 for moderate, <=0.05 for strong, and <=0.00285 for very strong evidence.
  • The consolidated case-evidence bundle and the directly available case files were reviewed for affected-relative non-carriers, parental testing, unaffected relatives, meioses, pedigree data, and a variant-specific co-segregation likelihood ratio; none was documented for this variant.
  • HUMU-40-1557-s001.xlsx converted full text was searched under c.7908T>A, p.Cys2636Ter, and p.C2636* with no matching entry; SupplementaryTables_V1.2.xlsx could not be converted to searchable full text.
Still missing
  • No affected-relative non-carrier observations, pedigree structure, meioses, or quantitative co-segregation LR were provided.
  • HUMU-40-1557-s001.xlsx was searched for c.7908T>A, p.Cys2636Ter, and p.C2636*; no entry was found.
  • SupplementaryTables_V1.2.xlsx full text is unavailable; the declared ST7 Reference Set lookup for this variant cannot be verified.
  • The VCEP cautions that phenocopies and more than one pathogenic variant in a family can confound apparent lack of segregation; no family-level data were available to evaluate these issues.
Sources
cspec ↗vcep_humu_40_1557_s001vcep_supplementarytables_v1_2_2024_11_18
BP5 Not assessed: no exact-variant clinical-history LR was available for comparison with the BP5 Supporting threshold LR <=0.48. Details ▾Hide ▴
Reasoning

ENIGMA restricts BP5 to a combined multifactorial clinical likelihood ratio against pathogenicity, with the literal thresholds BP5 Supporting LR <=0.48, Moderate LR <=0.23, Strong LR <=0.05, and Very Strong LR <=0.00285; values >0.48 and <2.08 are neutral. The exact BRCA2 c.7908T>A variant is absent from PMID_31853058_BRCA2_clinical_history_LR.xlsx, so no clinical-history LR is available. Therefore no inequality with a substituted variant value can be performed, and BP5 cannot be assessed. The ClinVar expert-panel Pathogenic classification is not benign clinical-history evidence.

Rule
Use only combined multifactorial clinical LR against pathogenicity; BP5 Supporting <=0.48, Moderate <=0.23, Strong <=0.05, Very Strong <=0.00285; neutral zone >0.48 and <2.08.
Evidence considered
  • ENIGMA states the BP5 Supporting operator literally as LR <=0.48; Moderate <=0.23, Strong <=0.05, and Very Strong <=0.00285.
  • The exact variant was searched in the gene-specific clinical-history LR table and no BRCA2 c.7908T>A row was found, so an explicit substituted inequality cannot be evaluated.
  • The VCEP index limits PMID:31853058 to clinical-history LR use and identifies PMID:17924331 as methodology/context rather than an exact variant result.
Still missing
  • No exact BRCA2 c.7908T>A entry was found in PMID_31853058_BRCA2_clinical_history_LR.xlsx.
  • No exact-variant combined LR against pathogenicity was available from the supplied multifactorial sources.
Sources
cspec ↗vcep_pmid_31853058_brca2_clinical_history_lrPMID:31853058 ↗PMID:17924331 ↗
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/ANot applicable: c.7908T>A is a nonsense PTC, whereas ENIGMA PS1 requires a pathogenic same-amino-acid or same-splicing comparison. Details ▾Hide ▴
Reasoning

PS1 is not applicable. The variant is a nonsense PTC, NM_000059.4:c.7908T>A (p.Cys2636Ter), not a predicted missense substitution or a variant with the same predicted splicing impact as a pathogenic reference variant. The ENIGMA BRCA2 specification limits PS1 to missense protein-change comparisons or shared predicted splicing events. Exact searches for c.7908T>A, p.Cys2636Ter, and p.C2636* found no 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.

Rule
ENIGMA PS1 is restricted to same-amino-acid pathogenic missense comparisons or equivalent predicted splicing events; it does not apply to a nonsense PTC.
Evidence considered
  • ENIGMA BRCA2 PS1 rule: PS1 applies to predicted missense substitutions with a previously classified pathogenic variant acting through protein change, or to variants with the same predicted splicing impact as a pathogenic reference variant.
  • The case variant is annotated as NM_000059.4:c.7908T>A, NP_000050.3:p.(Cys2636Ter), a nonsense PTC.
Still missing
  • No exact c.7908T>A, p.Cys2636Ter, or p.C2636* entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.7908T>A, p.Cys2636Ter, or p.C2636* entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.7908T>A, p.Cys2636Ter, or p.C2636* entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
Sources
vcep_specifications_v1_2_2024_11_18
PS2 VCEPNot applicable: ENIGMA explicitly prohibits PS2 for BRCA2 because de novo occurrences are not calibrated for these commonly occurring cancers. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA2 VCEP specification explicitly states that PS2 is not to be used because BRCA1/2-related cancers occur relatively commonly and there is no information to calibrate the predictive capacity of de novo occurrences. The case materials also contain no documented confirmed-paternity de novo observation for NM_000059.4:c.7908T>A (p.Cys2636Ter; p.C2636*).

VCEP rule
Do not use PS2 for BRCA2 under ENIGMA VCEP specification v1.2.
Evidence considered
  • The ENIGMA BRCA2 VCEP specification states under PS2: "Do not use" because BRCA1/2-related cancers occur relatively commonly and there is no information to calibrate the predictive capacity of de novo occurrences.
  • The case evidence bundle was reviewed for proband, parental-testing, paternity, maternity, and de novo information for c.7908T>A, p.Cys2636Ter, and p.C2636*; no confirmed-paternity de novo observation was documented.
Still missing
  • No confirmed-paternity de novo observation is documented in the case materials; this does not change the VCEP prohibition on PS2.
Sources
cspec ↗
PM1 VCEPNot applicable: residue 2636 lies within the DNA-binding domain, but ENIGMA PM1 is missense-domain evidence and this variant is a nonsense PTC. Details ▾Hide ▴
Reasoning

PM1 is not applicable to this nonsense PTC. The ENIGMA BRCA2 framework uses PM1 for missense evidence involving clinically important functional domains or critical residues, whereas this variant is a protein-truncating change evaluated under the PVS1/PM5(PTC) pathway. The governing domain_tables object is empty, so no separate authoritative extracted domain list is available; the specification nevertheless defines the BRCA2 DNA-binding domain as amino acids 2481-3186, which includes residue 2636, but domain membership alone does not convert a nonsense PTC into PM1 evidence. Exact searches for c.7908T>A, p.Cys2636Ter, and p.C2636* found no entry in Specifications_V1.2_2024-11-18.docx.txt or Appendices_V1.2_2024-11-18.docx.txt.

VCEP rule
ENIGMA PM1 concerns pathogenic missense/domain evidence; a nonsense PTC does not receive PM1 solely because its termination residue lies within the DNA-binding domain.
Evidence considered
  • The ENIGMA specification defines the BRCA2 DNA-binding domain as aa 2481-3186; residue 2636 falls within that interval.
  • PM1 is a missense/domain criterion in the governing framework, while c.7908T>A produces the truncating protein change p.Cys2636Ter and is handled by PVS1/PM5(PTC) logic.
Still missing
  • No exact c.7908T>A, p.Cys2636Ter, or p.C2636* entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.7908T>A, p.Cys2636Ter, or p.C2636* entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • vcep_materials.json has an empty domain_tables object; no extracted authoritative domain-table entry was available beyond the governing specification text.
Sources
vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18
PM4 VCEPNot applicable: ENIGMA explicitly says not to use PM4, and this variant is a nonsense PTC rather than an in-frame indel or stop-loss change. Details ▾Hide ▴
Reasoning

PM4 is not applicable under the ENIGMA BRCA1/2 V1.2 specification, which explicitly states Do not use for protein-length changes due to in-frame insertions/deletions or stop-loss variants and treats this evidence within the bioinformatic framework. This variant is a nonsense PTC, not an in-frame insertion/deletion or stop-loss variant.

VCEP rule
ENIGMA BRCA1/2 V1.2 Table 1: PM4 do not use; the criterion is not applicable to nonsense PTCs.
Evidence considered
  • The ENIGMA V1.2 Table 1 entry for PM4 states Do not use and limits the criterion to protein-length changes from in-frame insertions/deletions in non-repeat regions or stop-loss variants.
  • The normalized consequence is nonsense, p.(Cys2636Ter), so it does not meet the variant-type definition for PM4.
Still missing
  • No exact c.7908T>A, p.Cys2636Ter, or p.C2636* entry was found in Specifications_V1.2_2024-11-18.docx.txt; the explicit PM4 not-applicable rule governs.
  • No exact c.7908T>A, p.Cys2636Ter, or p.C2636* entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.7908T>A, p.Cys2636Ter, or p.C2636* entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • No exact c.7908T>A, p.Cys2636Ter, or p.C2636* entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PM6 VCEPNot applicable: ENIGMA explicitly prohibits PM6 for BRCA2 because uncalibrated de novo occurrences cannot support this criterion. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA2 VCEP specification explicitly states that PM6 is not to be used because BRCA1/2-related cancers occur relatively commonly and there is no information to calibrate the predictive capacity of de novo occurrences without confirmed paternity and maternity. The case materials contain no documented de novo observation for NM_000059.4:c.7908T>A (p.Cys2636Ter; p.C2636*).

VCEP rule
Do not use PM6 for BRCA2 under ENIGMA VCEP specification v1.2.
Evidence considered
  • The ENIGMA BRCA2 VCEP specification states under PM6: "Do not use" because BRCA1/2-related cancers occur relatively commonly and there is no information to calibrate the predictive capacity of de novo occurrences.
  • The case evidence bundle was reviewed for proband, parental-testing, paternity, maternity, and de novo information for c.7908T>A, p.Cys2636Ter, and p.C2636*; no de novo observation was documented.
Still missing
  • No de novo observation without confirmed paternity and maternity is documented in the case materials; this does not change the VCEP prohibition on PM6.
Sources
cspec ↗
PP2 VCEPNot applicable: ENIGMA marks PP2 not applicable, and this variant is a nonsense PTC rather than a missense change. Details ▾Hide ▴
Reasoning

PP2 is not applicable. The ENIGMA BRCA2 specification marks PP2 as not applicable, and the generic PP2 definition concerns missense variants in a gene with a low rate of benign missense variation where missense is a common disease mechanism. This case is a nonsense PTC, not a missense variant. Exact searches for c.7908T>A, p.Cys2636Ter, and p.C2636* found no entry in Specifications_V1.2_2024-11-18.docx.txt or Appendices_V1.2_2024-11-18.docx.txt.

VCEP rule
ENIGMA BRCA2 PP2 is not applicable; generic PP2 is also restricted to missense variants.
Evidence considered
  • The governing ENIGMA BRCA2 framework explicitly marks PP2 as Not Applicable.
  • The variant consequence is nonsense/PTC, whereas PP2 is defined for missense variants.
Still missing
  • No exact c.7908T>A, p.Cys2636Ter, or p.C2636* entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.7908T>A, p.Cys2636Ter, or p.C2636* entry was found in Appendices_V1.2_2024-11-18.docx.txt.
Sources
vcep_specifications_v1_2_2024_11_18
PP3 N/ANot applicable: the nonsense variant p.(Cys2636Ter) is outside the VCEP PP3 scope, which covers missense, in-frame, silent, or eligible intronic variants. Details ▾Hide ▴
Reasoning

The variant is a nonsense change, NM_000059.4:c.7908T>A, producing p.(Cys2636Ter), and is therefore outside the ENIGMA BRCA2 PP3 computational-evidence scope for missense, in-frame, silent, or eligible intronic variants. The governing specification also states not to apply PP3 when PVS1 is met. SpliceAI and other predictor scores were not evaluated for this out-of-scope criterion. No exact entry for c.7908T>A, p.Cys2636Ter, or p.C2636* was found in Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.

Rule
ENIGMA BRCA2 PP3 is limited to specified missense, in-frame, silent, and eligible intronic variants; do not apply PP3 if PVS1 is met.
Evidence considered
  • The ENIGMA BRCA2 specification defines PP3 for missense/in-frame variants based on protein impact or for eligible silent/intronic variants based on predicted splicing, and states not to apply PP3 if PVS1 is met.
  • Case normalization identifies NM_000059.4:c.7908T>A as the nonsense variant NP_000050.3:p.(Cys2636Ter), also represented as p.(C2636*).
Still missing
  • 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 PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗
BP1 N/ANot applicable: SpliceAI max delta 0.023 is low, but ENIGMA BP1 requires a silent, missense, or in-frame variant, not a nonsense PTC. Details ▾Hide ▴
Reasoning

BP1 is not applicable. The ENIGMA BRCA2 rule requires a silent, missense, or in-frame insertion/deletion/delins variant outside a clinically important domain with SpliceAI at or below 0.1; this variant is a nonsense PTC. Although the case SpliceAI maximum delta is 0.023, that prediction cannot satisfy BP1 because the required variant class is absent. Exact searches for c.7908T>A, p.Cys2636Ter, and p.C2636* found no entry in Specifications_V1.2_2024-11-18.docx.txt or Appendices_V1.2_2024-11-18.docx.txt.

Rule
Apply BP1 only to eligible silent, missense, or in-frame variants outside the relevant domain with SpliceAI <=0.1; do not apply it to nonsense PTCs.
Evidence considered
  • ENIGMA BP1 requires a silent, missense, or in-frame insertion/deletion/delins variant outside a clinically important domain and SpliceAI <=0.1.
  • The case SpliceAI maximum delta is 0.023, but the variant is a nonsense PTC and therefore fails BP1's required consequence class.
Still missing
  • No exact c.7908T>A, p.Cys2636Ter, or p.C2636* entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.7908T>A, p.Cys2636Ter, or p.C2636* entry was found in Appendices_V1.2_2024-11-18.docx.txt.
Sources
vcep_specifications_v1_2_2024_11_18spliceai ↗
BP2 VCEPNot applicable: ENIGMA BRCA2 V1.2 explicitly prohibits BP2 and permits it only in the context of BS2. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA1/2 Specification V1.2 explicitly states that BP2 is not to be used and is applied only in the context of BS2. Consequently, observations of this variant in trans with a pathogenic variant in a fully penetrant dominant disorder, or in cis with a pathogenic variant in any inheritance pattern, do not generate BP2 under the BRCA2 VCEP framework. The target variant was not found under c.7908T>A, p.Cys2636Ter, or p.C2636* in Specifications_V1.2_2024-11-18.docx.txt.

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; ENIGMA BRCA2 V1.2: do not use, applied only in the context of BS2.
Evidence considered
  • ENIGMA BRCA1/2 Specification V1.2 Table 1 lists BP2 as 'Do not use' and states that it is applied only in the context of BS2.
  • Because BP2 is prohibited by the governing VCEP specification, no phase or co-occurrence observation can satisfy BP2 for this BRCA2 assessment.
Still missing
  • No entry for c.7908T>A, p.Cys2636Ter, or p.C2636* was found in /Users/gs_agent/LYFESCI_HERMES_v9/vcep_db/BRCA2/fulltext/Specifications_V1.2_2024-11-18.docx.txt.
Sources
cspec ↗
BP3 VCEPNot applicable: BP3 concerns in-frame indels in repetitive regions, whereas this variant is a nonsense substitution producing p.Cys2636Ter. Details ▾Hide ▴
Reasoning

BP3 is not applicable because the variant is a nonsense substitution producing a premature termination codon, not an in-frame deletion or insertion in a repetitive region. The ENIGMA framework does not provide a BP3 application for this consequence, and no repeat-region context can convert a truncating allele into a BP3-eligible in-frame indel.

VCEP rule
BP3 is not applicable to a nonsense PTC; the ENIGMA V1.2 framework supplies no BP3 rule for this consequence.
Evidence considered
  • The variant is normalized as a nonsense substitution, NM_000059.4:c.7908T>A, p.(Cys2636Ter)/p.(C2636*), rather than an in-frame insertion or deletion.
  • BP3 therefore cannot be applied regardless of local sequence repetition; no BP3-eligible repeat-region protein-length change is present.
Still missing
  • No exact c.7908T>A, p.Cys2636Ter, or p.C2636* entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.7908T>A, p.Cys2636Ter, or p.C2636* entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.7908T>A, p.Cys2636Ter, or p.C2636* entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • No exact c.7908T>A, p.Cys2636Ter, or p.C2636* entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
BP4 N/ANot applicable: the nonsense variant p.(Cys2636Ter) is outside the VCEP BP4 scope, which covers missense, in-frame, silent, or eligible intronic variants. Details ▾Hide ▴
Reasoning

The variant is a nonsense change, NM_000059.4:c.7908T>A, producing p.(Cys2636Ter), and is outside the ENIGMA BRCA2 BP4 computational-evidence scope for missense, in-frame, silent, or eligible intronic variants. SpliceAI, BayesDel, and other predictor scores were not evaluated for this out-of-scope criterion. No exact entry for c.7908T>A, p.Cys2636Ter, or p.C2636* was found in Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.

Rule
ENIGMA BRCA2 BP4 is limited to specified missense, in-frame, silent, and eligible intronic variants; nonsense variants are outside scope.
Evidence considered
  • The ENIGMA BRCA2 specification defines BP4 for missense/in-frame variants with no predicted protein or splice impact, and for eligible silent or intronic variants with no predicted splice impact.
  • Case normalization identifies NM_000059.4:c.7908T>A as the nonsense variant NP_000050.3:p.(Cys2636Ter), also represented as p.(C2636*).
Still missing
  • 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 PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗
BP7 N/ANot applicable: BP7 is restricted to synonymous or eligible intronic variants, whereas this variant is the nonsense change p.(Cys2636Ter). Details ▾Hide ▴
Reasoning

BP7 applies only to synonymous or eligible intronic variants under the ENIGMA BRCA2 specification. This variant is a nonsense change, NM_000059.4:c.7908T>A, producing p.(Cys2636Ter), so BP7 is not applicable before any splice-prediction assessment. No exact entry for c.7908T>A, p.Cys2636Ter, or p.C2636* was found in Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.

Rule
ENIGMA BRCA2 BP7 applies only to synonymous or eligible intronic variants; nonsense variants are outside scope.
Evidence considered
  • The ENIGMA BRCA2 specification limits BP7 to silent variants and eligible intronic variants when the applicable splice-impact condition is met.
  • Case normalization identifies NM_000059.4:c.7908T>A as the nonsense variant NP_000050.3:p.(Cys2636Ter), also represented as p.(C2636*).
Still missing
  • 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 PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗

Identifiers

Gene
BRCA2
Transcript
NM_000059.4
Coding (HGVS c.)
NM_000059.4:c.7908T>A
Protein (HGVS p.)
NP_000050.3:p.(Cys2636Ter)
GRCh38
chr13:32362625 T>A
GRCh37
chr13:32936762 T>A
Location and type
Exon 17 · nonsense
ClinVar
52433

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 -33 bp
0.020
SpliceAI acceptor gainat -57 bp
0.000
SpliceAI donor lossat +68 bp
0.023
SpliceAI donor gainat +67 bp
0.000
Pangolin splice lossmagnitude shown
-0.245
Pangolin splice gain
0.003

Other predictors

REVEL
Not available
BayesDel
0.466

How the predictions were used

PP3 N/ANot applicable: the nonsense variant p.(Cys2636Ter) is outside the VCEP PP3 scope, which covers missense, in-frame, silent, or eligible intronic variants. Details ▾Hide ▴
Reasoning

The variant is a nonsense change, NM_000059.4:c.7908T>A, producing p.(Cys2636Ter), and is therefore outside the ENIGMA BRCA2 PP3 computational-evidence scope for missense, in-frame, silent, or eligible intronic variants. The governing specification also states not to apply PP3 when PVS1 is met. SpliceAI and other predictor scores were not evaluated for this out-of-scope criterion. No exact entry for c.7908T>A, p.Cys2636Ter, or p.C2636* was found in Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.

Rule
ENIGMA BRCA2 PP3 is limited to specified missense, in-frame, silent, and eligible intronic variants; do not apply PP3 if PVS1 is met.
Evidence considered
  • The ENIGMA BRCA2 specification defines PP3 for missense/in-frame variants based on protein impact or for eligible silent/intronic variants based on predicted splicing, and states not to apply PP3 if PVS1 is met.
  • Case normalization identifies NM_000059.4:c.7908T>A as the nonsense variant NP_000050.3:p.(Cys2636Ter), also represented as p.(C2636*).
Still missing
  • 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 PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗
BP4 N/ANot applicable: the nonsense variant p.(Cys2636Ter) is outside the VCEP BP4 scope, which covers missense, in-frame, silent, or eligible intronic variants. Details ▾Hide ▴
Reasoning

The variant is a nonsense change, NM_000059.4:c.7908T>A, producing p.(Cys2636Ter), and is outside the ENIGMA BRCA2 BP4 computational-evidence scope for missense, in-frame, silent, or eligible intronic variants. SpliceAI, BayesDel, and other predictor scores were not evaluated for this out-of-scope criterion. No exact entry for c.7908T>A, p.Cys2636Ter, or p.C2636* was found in Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.

Rule
ENIGMA BRCA2 BP4 is limited to specified missense, in-frame, silent, and eligible intronic variants; nonsense variants are outside scope.
Evidence considered
  • The ENIGMA BRCA2 specification defines BP4 for missense/in-frame variants with no predicted protein or splice impact, and for eligible silent or intronic variants with no predicted splice impact.
  • Case normalization identifies NM_000059.4:c.7908T>A as the nonsense variant NP_000050.3:p.(Cys2636Ter), also represented as p.(C2636*).
Still missing
  • 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 PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗
BP7 N/ANot applicable: BP7 is restricted to synonymous or eligible intronic variants, whereas this variant is the nonsense change p.(Cys2636Ter). Details ▾Hide ▴
Reasoning

BP7 applies only to synonymous or eligible intronic variants under the ENIGMA BRCA2 specification. This variant is a nonsense change, NM_000059.4:c.7908T>A, producing p.(Cys2636Ter), so BP7 is not applicable before any splice-prediction assessment. No exact entry for c.7908T>A, p.Cys2636Ter, or p.C2636* was found in Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.

Rule
ENIGMA BRCA2 BP7 applies only to synonymous or eligible intronic variants; nonsense variants are outside scope.
Evidence considered
  • The ENIGMA BRCA2 specification limits BP7 to silent variants and eligible intronic variants when the applicable splice-impact condition is met.
  • Case normalization identifies NM_000059.4:c.7908T>A as the nonsense variant NP_000050.3:p.(Cys2636Ter), also represented as p.(C2636*).
Still missing
  • 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 PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). BayesDel score = 0.466048.

8 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.
    This paper does not mention or experimentally test BRCA2 c.7908T>A or p.C2636*. It reports that C-terminal BRCA2 truncations lacking nuclear localization signals are excluded from the nucleus, but the experiments concern deletion constructs and BRCA2-6174delT rather than this variant.
    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, ‘BRCA2 NLSs Reside in the Extreme C Terminus,’ paragraph 4

  • BRCA2 is required for homology-directed repair of chromosomal breaks.
    This paper does not mention or experimentally test BRCA2 c.7908T>A or p.C2636*. It reports reduced homology-directed repair in cells carrying BRCA2 c.6174delT or mouse Brca2 exon 27 deletions, which are different variants and models.
    Does not name this variant
    PMID 11239455 ↗
    Quoted passage
    Thus, BRCA2 is essential for efficient homology-directed repair, presumably in conjunction with the Rad51 recombinase.

    Summary; Results and Discussion

  • A new mutation of BRCA2 gene in an Italian healthy woman with familial breast cancer history.
    This paper does not mention or experimentally test BRCA2 c.7908T>A or p.C2636*. It reports a different BRCA2 insertion causing a truncated protein and impaired nuclear localization.
    Does not name this variant
    PMID 20878484 ↗
    Quoted passage
    this nuclear truncated protein is non-functional: because it really cannot perform a translocation into the nucleus.

    Results and Discussion; Conclusion

  • BRCA1 and BRCA2: different roles in a common pathway of genome protection.
    This review does not mention or experimentally test BRCA2 c.7908T>A or p.C2636*. It summarizes BRCA2 biology, including defective RAD51 recruitment and homologous-recombination repair in BRCA2-deficient cells, without variant-specific assay data.
    Does not name this variant
    PMID 22193408 ↗
    Quoted passage
    BRCA2-deficient cells are defective in recruiting RAD51 to sites of DSBs and in repairing DSBs by HR.

    Section: ‘BRCA2, HR and replication fidelity’

  • A comprehensive focus on global spectrum of BRCA1 and BRCA2 mutations in breast cancer.
    This review does not explicitly mention or experimentally test BRCA2 c.7908T>A or p.C2636*. It describes premature-stop mutations and critical C-terminal BRCA2 domains at the gene level, not a calibrated assay result for this variant.
    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,’ page 3

  • Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.
    Borg A et al. · 2010
    This paper does not explicitly mention or functionally test BRCA2 c.7908T>A or p.C2636*. It describes general criteria classifying most BRCA2 nonsense variants as deleterious, with exceptions near the 3-prime end, but this is not a variant-specific functional assay result.
    Does not name this variant
    PMID 20104584 ↗
    Quoted passage
    all frameshift and nonsense variants with the exception of the neutral stop codon BRCA2 c.9976A>T (BIC: K3326X) (Mazoyer et al., 1996), and other variants located 3′ thereof

    Materials and Methods, Definition of deleterious mutations

  • Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium.
    No paper-specific finding is recorded.
    PMID 31672839 ↗
  • American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility.
    American Society of Clinical Oncology · 2003
    No paper-specific finding is recorded.
    PMID 12692171 ↗

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 0.023 Open source ↗
ClinVar 4 Pathogenic 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 has been reported in ClinVar as Pathogenic (4 clinical laboratories) and as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel). (ClinVarID = 52433)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). BayesDel score = 0.466048.

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.