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BRCA2c.6698C>TUncertain significance
Print report
Variant interpretation report

BRCA2 c.6698C>T, p.(Ala2233Val)

NM_000059.4:c.6698C>T NP_000050.3:p.(Ala2233Val) Missense · exon 11 View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

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

Uncertain.The recorded classification is uncertain significance.

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: 0 Benign evidence criteria: 1
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 1
BP1Strong
BP1 · strong

Met, Strong: residue 2233 is outside BRCA2 critical domains and SpliceAI max delta 0.014 is below the <=0.1 no-splicing threshold.

Recorded classification: Uncertain significance

VUS: BP1 (Strong) is the only applied criterion and does not satisfy ENIGMA's Likely Benign combination rule without additional benign evidence.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1
gnomAD v2.1
Population frequency
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 ↗
No screenshot for this evidence
REVEL score
0.555 recorded score

Recorded REVEL score: 0.555. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied
ClinVar submissions
1 reported laboratory submissions

1 Likely benign. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA2, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
2 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV66448396, n = 2 times).

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: 1 met · 5 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

For NM_000059.4:c.6698C>T (NP_000050.3:p.(Ala2233Val)), the governing ENIGMA BRCA2 V1.2 framework makes PVS1, PM4, and BP3 unavailable for this missense consequence.

No criterion in this group is met; no evidence from these criteria is contributed to variant classification.

For BRCA2 c.6698C>T (p.Ala2233Val), the governing ENIGMA VCEP framework makes PM1, PM5, and PP2 not applicable; PS1 is not met because no established pathogenic same-amino-acid comparator was identified.

BP1_Strong is met because residue 2233 lies outside the specified critical domains and SpliceAI maximum delta is 0.014, below 0.1.

The variant is missense, so REVEL is the sole applicable PP3/BP4 predictor path and BP7 is not applicable.

REVEL 0.555 is below the supporting PP3 threshold of 0.644 and above the supporting BP4 threshold of 0.29, so neither computational code is met.

Population evidence shows absence from the governing non-cancer gnomAD subsets, excluding BA1 and BS1; PM2 remains unassigned pending the required regional depth >=25, and BS2 lacks qualifying patient-level observations.

Met · 1

BP1 StrongMet, Strong: residue 2233 is outside BRCA2 critical domains and SpliceAI max delta 0.014 is below the <=0.1 no-splicing threshold. Details ▾Hide ▴
Reasoning

ENIGMA specifies BP1_Strong for a missense variant outside a potentially clinically important functional domain when no splicing is predicted; missense prediction is not applicable. The variant is p.Ala2233Val at residue 2233, outside the specified BRCA2 PALB2-binding domain (aa 10-40) and DNA-binding domain (aa 2481-3186). SpliceAI reports a maximum delta score of 0.014, which is below the ENIGMA no-splicing threshold of 0.1. All BP1_Strong prerequisites are met.

Rule
Apply BP1_Strong for a missense variant outside a potentially clinically important functional domain and with no predicted splicing impact (SpliceAI <=0.1); missense prediction is not applicable.
Evidence considered
  • ENIGMA BP1_Strong requires a missense variant outside a potentially clinically important functional domain with SpliceAI <=0.1; missense prediction is not applicable.
  • BRCA2 residue 2233 is outside the governing PALB2-binding domain at aa 10-40 and DNA-binding domain at aa 2481-3186.
  • SpliceAI maximum delta score is 0.014, below the ENIGMA <=0.1 no-splicing threshold.
Sources
cspec ↗spliceai ↗

Not met · 5 · evaluated, threshold not reached

PS1 Not met: no established pathogenic comparator producing p.Ala2233Val was identified, while the documented alternate p.Ala2233Asp is benign or uncertain. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 specification permits PS1 for a missense change producing the same amino-acid substitution as a previously established pathogenic variant, with the reference variant acting through protein change. Searches of Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, and Specifications_Table4_V1.2_2024-11-18.xlsx.txt found no entry for c.6698C>T, p.Ala2233Val, or p.A2233V. The governing VCEP supplementary and multifactorial tables contain the alternate same-residue change c.6698C>A, p.Ala2233Asp, but classify it as likely benign or uncertain rather than an established pathogenic comparator. No qualifying pathogenic same-amino-acid comparator was identified, so PS1 is not met.

Rule
Apply PS1 for a missense substitution producing the same amino-acid change as a previously classified pathogenic variant acting through protein change; ENIGMA BRCA2 specifies this criterion, but no qualifying comparator was found.
Evidence considered
  • The ENIGMA specification defines PS1 as the same amino-acid change as a previously established pathogenic variant and requires VCEP-classified pathogenicity for the comparator.
  • The VCEP full-text searches found no entry for c.6698C>T, p.Ala2233Val, or p.A2233V.
  • The alternate same-residue variant c.6698C>A (p.Ala2233Asp) is listed as likely benign in the ENIGMA supplementary table and as likely benign/uncertain in the multifactorial table, not as a pathogenic comparator.
Still missing
  • No c.6698C>T, p.Ala2233Val, or p.A2233V entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No c.6698C>T, p.Ala2233Val, or p.A2233V entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No c.6698C>T, p.Ala2233Val, or p.A2233V entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
Sources
cspec ↗vcep_supplementarytables_v1_2_2024_11_18vcep_humu_40_1557_s001
PP3 Not met: REVEL 0.555 is below the >=0.644 supporting PP3 threshold and remains in the non-informative gray zone. Details ▾Hide ▴
Reasoning

NM_000059.4:c.6698C>T (p.Ala2233Val) is a missense variant, so the applicable computational path is REVEL only. The REVEL score is 0.555, which is below the ClinGen SVI supporting PP3 threshold of >=0.644 (Pejaver et al. 2022, PMID:36413997) and therefore does not meet PP3. SpliceAI is not used for this missense PP3 decision, although its available maximum delta is 0.014. No variant-specific pre-assigned PP3 code was found in the searched ENIGMA Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, or PMID_22505045_Houdayer_2012_HumMutat.pdf files.

Rule
For a missense variant, evaluate PP3 using REVEL only; supporting PP3 requires REVEL >=0.644. A gray-zone result does not meet PP3 and does not permit substitution of SpliceAI.
Evidence considered
  • The case identifies NM_000059.4:c.6698C>T as the missense substitution NP_000050.3:p.(Ala2233Val).
  • The applicable missense predictor is REVEL; the recorded REVEL score is 0.555.
  • ClinGen SVI REVEL calibration assigns supporting PP3 at REVEL >=0.644 (Pejaver et al. 2022, PMID:36413997); 0.555 does not reach that threshold.
  • SpliceAI max delta 0.014 was not used for missense PP3 because PP3/BP4 evidence must come from the single consequence-matched path.
  • ENIGMA BRCA2 VCEP Specification v1.2 and Appendix J were consulted; no variant-specific pre-assigned PP3 entry was found in the searched governing files.
Still missing
  • No variant-specific pre-assigned PP3 entry was found in Specifications_V1.2_2024-11-18.docx.
  • No variant-specific pre-assigned PP3 entry was found in Appendices_V1.2_2024-11-18.docx.
  • No variant-specific pre-assigned PP3 entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.
Sources
cspec ↗revel
BA1 Not met: the variant is absent from required non-cancer gnomAD subsets, far below the ENIGMA BA1 threshold of FAF >0.001. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP specifies BA1 when maximum filter allele frequency exceeds 0.001 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. The case evidence reports the variant absent from GNOMAD_V2_1_NON_CANCER and GNOMAD_V3_1_NON_CANCER, so no allele frequency reaches the BA1 threshold. The variant is not a known pathogenic founder variant in the reviewed evidence. Exact searches for c.6698C>T, p.Ala2233Val, and p.A2233V found no variant row in Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or HUMU-40-1557-s001.xlsx.txt.

Rule
ENIGMA BRCA2 v1.2 BA1: maximum filter allele frequency >0.001 in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes; do not apply if read depth <20 or for a well-established pathogenic founder variant.
Evidence considered
  • ENIGMA BRCA2 VCEP v1.2 specifies BA1 for maximum filter allele frequency >0.001 in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes, assessed separately by exome and genome data.
  • The case evidence reports the variant absent from GNOMAD_V2_1_NON_CANCER and GNOMAD_V3_1_NON_CANCER; the all-comers gnomAD v2.1 and v4.1 queries are also absent.
  • ENIGMA Appendix G states that BA1 was calibrated using BRCA2 penetrance 0.69 from prospective data (PMID:28632866) and rounded to 0.001.
Still missing
  • No exact variant entry was found when searching Specifications_V1.2_2024-11-18.docx.txt.
  • No exact variant entry was found when searching Appendices_V1.2_2024-11-18.docx.txt.
  • No exact variant entry was found when searching HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18gnomad_v2 ↗gnomad_v4 ↗
BS1 Not met: the variant is absent from required non-cancer gnomAD subsets, below both ENIGMA BS1 thresholds of FAF >0.00002 and >0.0001. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP specifies BS1 Strong when maximum filter allele frequency is above 0.0001 and BS1 Supporting when it is above 0.00002 through 0.0001 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. The case evidence reports the variant absent from both required non-cancer datasets, so neither BS1 threshold is reached. Exact searches for c.6698C>T, p.Ala2233Val, and p.A2233V found no variant row in Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or HUMU-40-1557-s001.xlsx.txt.

Rule
ENIGMA BRCA2 v1.2 BS1: FAF >0.0001 for Strong, or >0.00002 to <=0.0001 for Supporting, in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes; do not apply if read depth <20.
Evidence considered
  • ENIGMA BRCA2 VCEP v1.2 specifies BS1 Strong for FAF >0.0001 and BS1 Supporting for FAF >0.00002 to <=0.0001 in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes.
  • The case evidence reports the variant absent from GNOMAD_V2_1_NON_CANCER and GNOMAD_V3_1_NON_CANCER; the all-comers gnomAD v2.1 and v4.1 queries are also absent.
  • ENIGMA Appendix G derives the BRCA2 BS1 threshold from prevalence 0.125, genetic heterogeneity 0.01, allelic heterogeneity 0.10, and penetrance 0.69, rounding the calculated 0.0000906 threshold to 0.0001.
Still missing
  • No exact variant entry was found when searching Specifications_V1.2_2024-11-18.docx.txt.
  • No exact variant entry was found when searching Appendices_V1.2_2024-11-18.docx.txt.
  • No exact variant entry was found when searching HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18gnomad_v2 ↗gnomad_v4 ↗
BP4 Not met: REVEL 0.555 exceeds the <=0.29 supporting BP4 threshold and is therefore a gray-zone missense result. Details ▾Hide ▴
Reasoning

NM_000059.4:c.6698C>T (p.Ala2233Val) is a missense variant, so the applicable computational path is REVEL only. The REVEL score is 0.555, which exceeds the supporting BP4 threshold of <=0.29 and lies in the gray zone; therefore BP4 is not met. SpliceAI is not substituted for this missense BP4 decision, although its available maximum delta is 0.014. No variant-specific pre-assigned BP4 code was found in the searched ENIGMA Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, or PMID_22505045_Houdayer_2012_HumMutat.pdf files.

Rule
For a missense variant, evaluate BP4 using REVEL only; supporting BP4 requires REVEL <=0.29. A gray-zone result does not meet BP4 and does not permit substitution of SpliceAI.
Evidence considered
  • The case identifies NM_000059.4:c.6698C>T as the missense substitution NP_000050.3:p.(Ala2233Val).
  • The applicable missense predictor is REVEL; the recorded REVEL score is 0.555.
  • ClinGen SVI REVEL calibration assigns supporting BP4 at REVEL <=0.29 (Pejaver et al. 2022, PMID:36413997); 0.555 exceeds that threshold and is not benign-supportive.
  • SpliceAI max delta 0.014 was not used for missense BP4 because PP3/BP4 evidence must come from the single consequence-matched path.
  • ENIGMA BRCA2 VCEP Specification v1.2 and Appendix J were consulted; no variant-specific pre-assigned BP4 entry was found in the searched governing files.
Still missing
  • No variant-specific pre-assigned BP4 entry was found in Specifications_V1.2_2024-11-18.docx.
  • No variant-specific pre-assigned BP4 entry was found in Appendices_V1.2_2024-11-18.docx.
  • No variant-specific pre-assigned BP4 entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.
Sources
cspec ↗revel

Not assessed · 10 · no assessment recorded

PS3 Not assessed: ENIGMA Table 9 contains no calibrated PS3 entry for c.6698C>T, p.Ala2233Val, or p.A2233V. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA2 V1.2 specification reserves PS3 for well-established functional studies measuring protein function or combined mRNA and protein effects, with calibrated variant-specific recommendations provided in Table 9. Exact searches for NM_000059.4:c.6698C>T, p.(Ala2233Val), and p.(A2233V) found no entry in Specifications_Table9_V1.2_2024-11-18.xlsx.txt; no variant-specific protein-function assay result was identified in the case evidence bundle or prefetch evidence. Therefore, PS3 cannot be assigned from the available evidence.

Rule
ENIGMA BRCA2 V1.2 PS3: well-established in vitro or in vivo functional studies supportive of a damaging effect, measured via protein only or mRNA and protein combined; use calibrated recommendations in Specifications Table 9.
Evidence considered
  • ENIGMA BRCA2 V1.2 specifies PS3 for well-established in vitro or in vivo functional studies measuring protein function alone or combined mRNA and protein effects, and directs curators to calibrated recommendations in Table 9.
  • Exact and alternate HGVS searches found no pre-assigned PS3 result for NM_000059.4:c.6698C>T, p.(Ala2233Val), or p.(A2233V) in the governing VCEP functional-assay table.
  • The case evidence identifies the variant as a missense change and provides SpliceAI max delta 0.014, but this is splice-prediction evidence and does not establish PS3 protein dysfunction under the governing rule.
Still missing
  • No exact variant entry was found in Specifications_Table9_V1.2_2024-11-18.xlsx.txt after searching c.6698C>T, p.Ala2233Val, p.A2233V, 6698, and 2233.
  • No exact variant entry was found in Appendices_V1.2_2024-11-18.docx.txt after searching c.6698C>T, p.Ala2233Val, p.A2233V, 6698, and 2233.
  • No exact variant entry was found in HUMU-40-1557-s001.xlsx.txt after searching c.6698C>T, p.Ala2233Val, p.A2233V, 6698, and 2233.
  • No exact variant entry was found in Specifications_V1.2_2024-11-18.docx.txt after searching c.6698C>T, p.Ala2233Val, p.A2233V, 6698, and 2233.
  • A variant-specific, well-established protein-function assay with validated controls and calibrated interpretation was not identified in the supplied case evidence.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_specifications_table9_v1_2_2024_11_18
PS4 Not assessed: no exact-variant case-control p-value, OR, or confidence interval was available to test p <=0.05, OR >=4, and lower confidence interval >2.0. Details ▾Hide ▴
Reasoning

ENIGMA BRCA2 V1.2 specifies PS4 for case-control studies with p-value <=0.05 and OR >=4, with the lower confidence interval excluding 2.0; the governing text also prefers a case-control LR under PP4/BP5 when available. Searches of SupplementaryTables_V1.2.xlsx, HUMU-40-1557-s001.xlsx, and the exact-variant notations c.6698C>T, p.Ala2233Val, and p.A2233V found no variant row. The SupplementaryTables_V1.2.xlsx full text is unavailable, so its ST7 result cannot be verified. PMID:31911673 discusses an exon 10-11 regional coldspot but does not mention this exact variant and does not supply an exact-variant case-control p-value, OR, or confidence interval. Therefore PS4 cannot be assessed from the available exact-variant evidence.

Rule
Case-control studies; p-value <=0.05 and OR >=4 (lower confidence interval excludes 2.0).
Evidence considered
  • ENIGMA V1.2 PS4 rule: case-control p-value <=0.05 and OR >=4, with the lower confidence interval excluding 2.0.
  • The exact variant notations c.6698C>T, p.Ala2233Val, and p.A2233V were searched in the governing converted VCEP files; no exact row was found.
  • PMID:31911673 reports a regional BRCA2 exon 10-11 coldspot with estimated pathogenicity odds ratio <0.01, but explicitly does not mention p.A2233V and is not an exact-variant case-control result.
Still missing
  • No exact-variant entry found in HUMU-40-1557-s001.xlsx for c.6698C>T, p.Ala2233Val, or p.A2233V.
  • No exact-variant entry found in Specifications_V1.2_2024-11-18.docx.txt for c.6698C>T, p.Ala2233Val, or p.A2233V.
  • No exact-variant entry found in PMID_31853058_BRCA2_clinical_history_LR.xlsx.txt for c.6698C>T, p.Ala2233Val, or p.A2233V; this file is for PP4/BP5 clinical-history LR rather than PS4 case-control testing.
  • SupplementaryTables_V1.2.xlsx full text is unavailable; ST7 cannot be searched or verified.
  • No exact-variant case-control p-value, OR, or lower confidence interval is available in the case evidence.
Sources
cspec ↗vcep_humu_40_1557_s001vcep_supplementarytables_v1_2_2024_11_18PMID:31911673 ↗
PM2 Not assessed: the variant is absent from required non-cancer gnomAD subsets, but the ENIGMA PM2 rule requires regional read depth >=25 and no depth value is available. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP specifies PM2 Supporting when the variant is absent from gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes and the surrounding region has average read depth at least 25. The case evidence reports absence from both required datasets, but supplies no regional read-depth value or quality-control depth evidence. Because the mandatory depth condition cannot be verified, PM2 is not assigned. Exact searches for c.6698C>T, p.Ala2233Val, and p.A2233V found no variant row in Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or HUMU-40-1557-s001.xlsx.txt.

Rule
ENIGMA BRCA2 v1.2 PM2 Supporting: absent from gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, with regional average read depth >=25; do not apply if depth is below 25 or the variant is an indel with low recall.
Evidence considered
  • ENIGMA BRCA2 VCEP v1.2 specifies PM2 Supporting for absence from gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, provided the surrounding region has average read depth >=25.
  • The case evidence reports the variant absent from GNOMAD_V2_1_NON_CANCER and GNOMAD_V3_1_NON_CANCER, but both records contain empty source_data and no depth metric.
  • ENIGMA Appendix G recommends read depth >25 for PM2 Supporting and exclusion of data that failed quality control.
Still missing
  • Regional average read depth and explicit quality-control status are not available for the variant in the collected gnomAD evidence.
  • No exact variant entry was found when searching Specifications_V1.2_2024-11-18.docx.txt.
  • No exact variant entry was found when searching Appendices_V1.2_2024-11-18.docx.txt.
  • No exact variant entry was found when searching HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18gnomad_v2 ↗gnomad_v4 ↗
PM3 Not assessed: no documented Fanconi-anemia phenotype or phased pathogenic BRCA2 variant in trans/cis is available for PM3 scoring. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP specification limits PM3 to patients with a phenotype consistent with BRCA1/2-related Fanconi anemia and a co-occurrent pathogenic or likely pathogenic variant in the same gene; the available case evidence documents no Fanconi-anemia phenotype, affected proband observation, phase, or pathogenic variant in trans/cis. The governing Specifications_V1.2_2024-11-18.docx full text was searched for c.6698C>T, p.Ala2233Val, and p.A2233V, with no variant-specific entry found.

Rule
ENIGMA BRCA2 VCEP Specifications v1.2 PM3_VariableWeight: Fanconi-anemia phenotype plus a co-occurrent pathogenic/likely pathogenic variant in the same gene; Table 6 assigns points by phase and phenotype.
Evidence considered
  • ENIGMA BRCA2 VCEP PM3 rule: apply only for a patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi anemia and a co-occurrent variant in the same gene; PM3 strength is assigned from Table 6 points based on phase and phenotype.
  • Table 6 assigns 2 points when the variant under assessment is in trans or homozygous with a pathogenic/likely pathogenic variant in a phenotype-consistent Fanconi-anemia patient, and 1 point when phase is unknown; PM3 requires 2 points and PM3_Supporting requires 1 point.
  • The case evidence contains no documented Fanconi-anemia presentation, chromosome-breakage testing, co-occurring pathogenic/likely pathogenic BRCA2 variant, or phase determination for NM_000059.4:c.6698C>T.
Still missing
  • No affected-proband or Fanconi-anemia phenotype data, chromosome-breakage result, co-occurring BRCA2 pathogenic/likely pathogenic variant, or phase information was found in the case evidence.
  • Specifications_V1.2_2024-11-18.docx was searched for c.6698C>T, p.Ala2233Val, and p.A2233V; no variant-specific entry was found.
Sources
cspec ↗
PP1 Not assessed: no affected-relative genotypes or co-segregation LR are available, so the PP1 threshold of LR >=2.08 cannot be evaluated. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP requires quantitative co-segregation evidence from multiple affected family members and assigns PP1 Supporting at LR >=2.08, Moderate at LR >=4.3, Strong at LR >=18.7, and Very Strong at LR >=350. The case materials contain no proband-level pedigree, parental testing, meioses, affected-relative genotypes, or co-segregation LR for NM_000059.4:c.6698C>T (p.Ala2233Val/p.A2233V). The exact variant was not found in HUMU-40-1557-s001.xlsx, and no exact entry was found in the searchable SupplementaryTables text; the SupplementaryTables_V1.2.xlsx full-text conversion is unavailable, so that source remains a gap rather than evidence of absence.

Rule
PP1_VariableWeight: quantitative co-segregation LR >=2.08 for Supporting, >=4.3 for Moderate, >=18.7 for Strong, and >=350 for Very Strong; LR >0.48 and <2.08 is non-informative.
Evidence considered
  • ENIGMA BRCA2 VCEP Specification v1.2 requires quantitative co-segregation with disease in multiple affected family members and sets PP1 thresholds at LR >=2.08 for Supporting, >=4.3 for Moderate, >=18.7 for Strong, and >=350 for Very Strong.
  • The consolidated case-evidence bundle and directly read case files provide no variant-specific pedigree, parental testing, affected-relative genotype, meiosis count, or co-segregation LR for this variant.
  • The exact variant notations c.6698C>T, p.Ala2233Val, and p.A2233V were searched in HUMU-40-1557-s001.xlsx converted full text without an exact match.
  • The exact variant notations were also searched in the available SupplementaryTables converted text without an exact match; the separately declared SupplementaryTables_V1.2.xlsx full-text conversion is unavailable.
Still missing
  • No case-specific pedigree, affected-relative testing, parental testing, meioses, or quantitative co-segregation likelihood ratio was provided.
  • No exact c.6698C>T, p.Ala2233Val, or p.A2233V entry was found in HUMU-40-1557-s001.xlsx after searching its converted full text.
  • No exact c.6698C>T, p.Ala2233Val, or p.A2233V entry was found in the available searchable SupplementaryTables_V1.2_2024-11-18.xlsx text; the declared SupplementaryTables_V1.2.xlsx full-text conversion is unavailable and must be treated as a conversion gap, not as an empty file.
Sources
cspec ↗vcep_humu_40_1557_s001vcep_supplementarytables_v1_2_2024_11_18
PP4 Not assessed: no exact-variant combined clinical LR was available to test PP4 thresholds of >=2.08, >=4.3, >=18.7, or >=350. Details ▾Hide ▴
Reasoning

ENIGMA V1.2 restricts PP4 to clinically calibrated multifactorial likelihood evidence and specifies LR >=2.08 for Supporting, LR >=4.3 for Moderate, LR >=18.7 for Strong, and LR >=350 for Very Strong. The exact BRCA2 clinical-history table PMID_31853058_BRCA2_clinical_history_LR.xlsx.txt was searched for c.6698C>T, p.Ala2233Val, and p.A2233V without an exact entry, and no combined clinical LR is supplied elsewhere in the case bundle. Without an exact clinical LR, no PP4 strength can be assigned.

Rule
Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data: PP4 LR >=2.08:1; PP4_Moderate LR >=4.3:1; PP4_Strong LR >=18.7:1; PP4_Very Strong LR >=350:1.
Evidence considered
  • ENIGMA V1.2 PP4 thresholds are LR >=2.08 Supporting, >=4.3 Moderate, >=18.7 Strong, and >=350 Very Strong.
  • The gene-specific BRCA2 clinical-history LR table was searched by the exact coding and protein notations and yielded no exact variant row.
  • The VCEP index states that PP4 uses combined clinically calibrated multifactorial LR evidence, not a general phenotype description alone.
Still missing
  • No exact-variant entry found in PMID_31853058_BRCA2_clinical_history_LR.xlsx.txt for c.6698C>T, p.Ala2233Val, or p.A2233V.
  • No exact-variant combined multifactorial clinical LR, including family-history, pathology, co-occurrence, or segregation components, is available in the case evidence.
  • No exact-variant entry found in PMID_17924331_Easton_2007_AJHG.pdf.txt for c.6698C>T, p.Ala2233Val, or p.A2233V.
Sources
cspec ↗vcep_pmid_31853058_brca2_clinical_history_lrvcep_pmid_17924331_easton_2007_ajhg
BS2 Not assessed: no qualifying patient-level homozygote or trans co-occurrence with age and Fanconi-anemia phenotype data is available for BS2 point scoring. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP applies BS2 through point-scored observations of the variant in trans with a pathogenic or likely pathogenic BRCA2 variant, or as a homozygote, in phenotyped patients unlikely to have Fanconi anemia. The collected case evidence contains no individual-level homozygote, phase, co-occurrence, age, cancer-onset, or Fanconi-anemia phenotype observation for this variant. The VCEP explicitly excludes homozygote observations from gnomAD frequency data from BS2 because such observations are handled by BA1 or BS1. Therefore BS2 cannot be assigned from the available evidence. Exact searches for c.6698C>T, p.Ala2233Val, and p.A2233V found no variant row in Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or HUMU-40-1557-s001.xlsx.txt.

Rule
ENIGMA BRCA2 v1.2 BS2: assign points only from qualifying phenotyped patient observations with the variant in trans with a P/LP variant or as a homozygote; BS2 Strong requires >=4 points, Moderate 2 points, Supporting 1 point.
Evidence considered
  • ENIGMA BRCA2 VCEP v1.2 requires BS2 point scoring for a variant in trans with a P/LP variant or as a homozygote in a presumed Fanconi-anemia-unaffected patient, with points determined by age and cancer status.
  • ENIGMA Appendix H assigns BS2 at 4 or more points, BS2 Moderate at 2 points, and BS2 Supporting at 1 point.
  • ENIGMA Appendix H states that gnomAD homozygote observations are not used for BS2 frequency coding and are instead captured by BA1 or BS1.
Still missing
  • No qualifying patient-level homozygote or trans co-occurrence record with phase and Fanconi-anemia-relevant phenotype was identified.
  • No exact variant entry was found when searching Specifications_V1.2_2024-11-18.docx.txt.
  • No exact variant entry was found when searching Appendices_V1.2_2024-11-18.docx.txt.
  • No exact variant entry was found when searching HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18
BS3 Not assessed: ENIGMA Table 9 contains no calibrated BS3 entry for c.6698C>T, p.Ala2233Val, or p.A2233V. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA2 V1.2 specification reserves BS3 for well-established functional studies showing no damaging effect on protein function, measured by protein alone or combined mRNA and protein, with calibrated variant-specific recommendations provided in Table 9. Exact searches for NM_000059.4:c.6698C>T, p.(Ala2233Val), and p.(A2233V) found no entry in Specifications_Table9_V1.2_2024-11-18.xlsx.txt; no variant-specific benign protein-function assay result was identified in the case evidence bundle or prefetch evidence. Therefore, BS3 cannot be assigned from the available evidence.

Rule
ENIGMA BRCA2 V1.2 BS3: well-established in vitro or in vivo functional studies showing no damaging effect on protein function, measured via protein only or mRNA and protein combined; use calibrated recommendations in Specifications Table 9.
Evidence considered
  • ENIGMA BRCA2 V1.2 specifies BS3 for well-established in vitro or in vivo functional studies showing no damaging effect on protein function, measured via protein only or mRNA and protein combined, and directs curators to calibrated recommendations in Table 9.
  • Exact and alternate HGVS searches found no pre-assigned BS3 result for NM_000059.4:c.6698C>T, p.(Ala2233Val), or p.(A2233V) in the governing VCEP functional-assay table.
  • The absence of a variant-specific functional assay result prevents assigning benign functional evidence; the available SpliceAI max delta 0.014 is not a protein-function assay and cannot establish BS3.
Still missing
  • No exact variant entry was found in Specifications_Table9_V1.2_2024-11-18.xlsx.txt after searching c.6698C>T, p.Ala2233Val, p.A2233V, 6698, and 2233.
  • No exact variant entry was found in Appendices_V1.2_2024-11-18.docx.txt after searching c.6698C>T, p.Ala2233Val, p.A2233V, 6698, and 2233.
  • No exact variant entry was found in HUMU-40-1557-s001.xlsx.txt after searching c.6698C>T, p.Ala2233Val, p.A2233V, 6698, and 2233.
  • No exact variant entry was found in Specifications_V1.2_2024-11-18.docx.txt after searching c.6698C>T, p.Ala2233Val, p.A2233V, 6698, and 2233.
  • A variant-specific, well-established protein-function assay with validated controls and calibrated interpretation was not identified in the supplied case evidence.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_specifications_table9_v1_2_2024_11_18
BS4 Not assessed: no affected-relative non-segregation data or benign-direction LR are available, so the BS4 threshold of LR <=0.48 cannot be evaluated. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP requires quantitative evidence of lack of segregation in affected family members and assigns BS4 Supporting at LR <=0.48, Moderate at LR <=0.23, Strong at LR <=0.05, and Very Strong at LR <=0.00285. The case materials contain no non-segregating affected relatives, parental testing, meioses, or benign-direction co-segregation LR for NM_000059.4:c.6698C>T (p.Ala2233Val/p.A2233V). The exact variant was not found in HUMU-40-1557-s001.xlsx, and no exact entry was found in the searchable SupplementaryTables text; the SupplementaryTables_V1.2.xlsx full-text conversion is unavailable, so that source remains a gap rather than evidence of absence.

Rule
BS4_VariableWeight: quantitative lack-of-segregation LR <=0.48 for Supporting, <=0.23 for Moderate, <=0.05 for Strong, and <=0.00285 for Very Strong; LR >0.48 and <2.08 is non-informative.
Evidence considered
  • ENIGMA BRCA2 VCEP Specification v1.2 requires quantitative lack-of-segregation evidence and sets BS4 thresholds at LR <=0.48 for Supporting, <=0.23 for Moderate, <=0.05 for Strong, and <=0.00285 for Very Strong.
  • The consolidated case-evidence bundle and directly read case files provide no variant-specific affected-relative non-segregation, parental testing, meiosis count, or benign-direction co-segregation LR for this variant.
  • The exact variant notations c.6698C>T, p.Ala2233Val, and p.A2233V were searched in HUMU-40-1557-s001.xlsx converted full text without an exact match.
  • The exact variant notations were also searched in the available SupplementaryTables converted text without an exact match; the separately declared SupplementaryTables_V1.2.xlsx full-text conversion is unavailable.
Still missing
  • No case-specific pedigree, affected-relative testing, parental testing, meioses, or quantitative non-segregation likelihood ratio was provided.
  • No exact c.6698C>T, p.Ala2233Val, or p.A2233V entry was found in HUMU-40-1557-s001.xlsx after searching its converted full text.
  • No exact c.6698C>T, p.Ala2233Val, or p.A2233V entry was found in the available searchable SupplementaryTables_V1.2_2024-11-18.xlsx text; the declared SupplementaryTables_V1.2.xlsx full-text conversion is unavailable and must be treated as a conversion gap, not as an empty file.
Sources
cspec ↗vcep_humu_40_1557_s001vcep_supplementarytables_v1_2_2024_11_18
BP5 Not assessed: no exact-variant combined LR was available to test BP5's benign-direction thresholds of <=0.48, <=0.23, <=0.05, or <=0.00285. Details ▾Hide ▴
Reasoning

ENIGMA V1.2 restricts BP5 to combined multifactorial likelihood evidence against pathogenicity and literally specifies the benign-direction operators: BP5 Supporting LR <=0.48, Moderate LR <=0.23, Strong LR <=0.05, and Very Strong LR <=0.00285; combined LR >0.48 and <1.00 is not informative. The exact BRCA2 clinical-history LR table was searched for c.6698C>T, p.Ala2233Val, and p.A2233V without an exact entry, and no combined LR is available in the case evidence. Thus no BP5 strength can be assessed, despite the benign-direction thresholds.

Rule
Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data: BP5 LR <=0.48 to >0.23:1; BP5_Moderate LR <=0.23:1; BP5_Strong LR <=0.05:1; BP5_VeryStrong LR <=0.00285:1.
Evidence considered
  • ENIGMA V1.2 BP5 thresholds use the opposite direction: Supporting LR <=0.48, Moderate LR <=0.23, Strong LR <=0.05, and Very Strong LR <=0.00285.
  • The exact BRCA2 clinical-history LR table was searched by the exact coding and protein notations and yielded no exact variant row.
  • No combined clinical LR is available, so an explicit substituted inequality cannot be evaluated for this variant.
Still missing
  • No exact-variant entry found in PMID_31853058_BRCA2_clinical_history_LR.xlsx.txt for c.6698C>T, p.Ala2233Val, or p.A2233V.
  • No exact-variant combined multifactorial clinical LR against pathogenicity is available in the case evidence.
  • No exact-variant entry found in PMID_17924331_Easton_2007_AJHG.pdf.txt for c.6698C>T, p.Ala2233Val, or p.A2233V.
Sources
cspec ↗vcep_pmid_31853058_brca2_clinical_history_lrvcep_pmid_17924331_easton_2007_ajhg
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: c.6698C>T is a missense substitution, whereas ENIGMA PVS1 covers null or canonical splice-site loss-of-function variants. Details ▾Hide ▴
Reasoning

PVS1 is not applicable. On the governing ENIGMA BRCA2 VCEP framework, PVS1 is restricted to null consequences such as nonsense, frameshift, canonical donor/acceptor ±1,2 splice-site, initiation-codon, or exon deletion/duplication variants, including appropriately supported RNA-defined loss of function. NM_000059.4:c.6698C>T is a missense substitution, NP_000050.3:p.(Ala2233Val), with no canonical splice-site position and SpliceAI maximum delta 0.014; therefore it does not enter the PVS1 decision tree. The full-strength PVS1 literal strength requirement is not applicable because the criterion itself is not applicable.

Rule
ENIGMA BRCA2 V1.2 PVS1 applies to null or canonical ±1,2 splice-site loss-of-function variants; missense variants are outside the PVS1 decision tree.
Evidence considered
  • The ENIGMA BRCA2 VCEP specification defines PVS1 for null variants, including nonsense, frameshift, canonical donor/acceptor ±1,2 splice-site, initiation-codon, and exon deletion/duplication variants, with variable strength determined by its decision tree.
  • The case normalization identifies NM_000059.4:c.6698C>T as NP_000050.3:p.(Ala2233Val), consequence class missense, and not a canonical splice-consensus variant.
  • SpliceAI reports a maximum delta score of 0.014, providing no evidence that this missense substitution should be reclassified as a splice-disrupting null variant.
Still missing
  • No exact entry for c.6698C>T, p.Ala2233Val, or p.A2233V was found when searched in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact entry for c.6698C>T, p.Ala2233Val, or p.A2233V was found when searched in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact entry for c.6698C>T, p.Ala2233Val, or p.A2233V was found when searched in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • No exact entry for c.6698C>T, p.Ala2233Val, or p.A2233V was found when searched in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_specifications_table4_v1_2_2024_11_18spliceai ↗
PS2 VCEPNot applicable: ENIGMA BRCA2 v1.2 explicitly prohibits PS2 because de novo occurrence predictive capacity is uncalibrated. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA2 VCEP Specification v1.2 explicitly states that PS2 should not be used for BRCA1/2-related cancers because the predictive capacity of de novo occurrences has not been calibrated.

VCEP rule
PS2: Do not use; BRCA1/2-related cancers occur relatively commonly and there is no information to calibrate the predictive capacity of de novo occurrences.
Evidence considered
  • ENIGMA BRCA2 VCEP Specification v1.2 lists PS2 as 'Do not use' and states that no information is available to calibrate de novo occurrences for BRCA1/2-related cancers.
Sources
cspec ↗
PM1 VCEPNot applicable: ENIGMA BRCA2 explicitly prohibits PM1, and residue 2233 lies outside its listed amino-acid 10-40 and 2481-3186 domains. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA2 specification explicitly states that PM1 is not used and is considered as a component of bioinformatic analysis instead. The case vcep_materials.json domain_tables key is empty; the governing specification's listed BRCA2 clinically important domains are the PALB2-binding domain at amino acids 10-40 and DNA-binding domain at amino acids 2481-3186, neither of which includes residue 2233. PM1 is therefore not applicable under the governing framework.

VCEP rule
ENIGMA BRCA2 PM1: Do not use; consider as a component of bioinformatic analysis.
Evidence considered
  • The ENIGMA BRCA2 specification states: PM1, do not use; consider it as a component of bioinformatic analysis.
  • The specified BRCA2 clinically important domains are PALB2 binding amino acids 10-40 and DNA binding amino acids 2481-3186; residue 2233 is outside both.
  • vcep_materials.json contains an empty domain_tables object, so no additional authoritative domain-table entry applies.
Still missing
  • No c.6698C>T, p.Ala2233Val, or p.A2233V entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No c.6698C>T, p.Ala2233Val, or p.A2233V entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No c.6698C>T, p.Ala2233Val, or p.A2233V entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
Sources
cspec ↗vcep_appendices_v1_2_2024_11_18PMID:31911673 ↗
PM4 VCEPNot applicable: ENIGMA explicitly excludes PM4, and p.(Ala2233Val) changes one amino acid without altering protein length. Details ▾Hide ▴
Reasoning

PM4 is explicitly designated Not Applicable in the governing ENIGMA BRCA2 V1.2 criteria rules. The variant is a single amino-acid missense substitution, p.(Ala2233Val), with no protein-length change, in-frame insertion/deletion, or repeat-region alteration presented in the case evidence. PM4 therefore cannot be applied under this VCEP framework.

VCEP rule
ENIGMA BRCA2 V1.2 PM4: Not Applicable.
Evidence considered
  • The ENIGMA BRCA2 V1.2 rules list PM4 as Not Applicable.
  • The normalized consequence is missense, NP_000050.3:p.(Ala2233Val), which is a one-residue substitution and does not create a protein-length change or an in-frame indel consequence.
Still missing
  • No exact entry for c.6698C>T, p.Ala2233Val, or p.A2233V was found when searched in Specifications_V1.2_2024-11-18.docx.txt; the governing rule itself designates PM4 Not Applicable.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PM5 N/ANot applicable: ENIGMA repurposes PM5 for pathogenic PTC variants, whereas c.6698C>T produces the missense substitution p.Ala2233Val. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA2 specification explicitly states that classic missense PM5 is not used and is considered as a component of bioinformatic analysis. In this framework PM5 is repurposed as PM5_VariableWeight (PTC) for a protein termination codon variant in an exon where a different proven pathogenic PTC has been seen. This variant is missense, c.6698C>T p.Ala2233Val, not a PTC, and Table 4 does not provide a relevant missense PM5 assignment. PM5 is therefore not applicable.

Rule
ENIGMA BRCA2 PM5: Do not use classic missense PM5; use PM5_VariableWeight only for genomic PTC variants under the exon-specific Table 4 rules.
Evidence considered
  • ENIGMA states that classic missense PM5 is not used; its repurposed PM5_VariableWeight applies only to PTC variants.
  • The case variant is classified as missense and encodes p.Ala2233Val, so the PTC-specific PM5 rule cannot apply.
  • The governing Table 4 search found no entry for this missense variant.
Still missing
  • No c.6698C>T, p.Ala2233Val, or p.A2233V entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No c.6698C>T, p.Ala2233Val, or p.A2233V entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No c.6698C>T, p.Ala2233Val, or p.A2233V entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
Sources
cspec ↗vcep_appendices_v1_2_2024_11_18vcep_specifications_table4_v1_2_2024_11_18
PM6 VCEPNot applicable: ENIGMA BRCA2 v1.2 explicitly prohibits PM6 because de novo occurrence predictive capacity is uncalibrated. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA2 VCEP Specification v1.2 explicitly states that PM6 should not be used for BRCA1/2-related cancers because the predictive capacity of de novo occurrences has not been calibrated, even when paternity is unconfirmed.

VCEP rule
PM6: Do not use; BRCA1/2-related cancers occur relatively commonly and there is no information to calibrate the predictive capacity of de novo occurrences.
Evidence considered
  • ENIGMA BRCA2 VCEP Specification v1.2 lists PM6 as 'Do not use' and gives the same lack of calibration rationale as for PS2.
Sources
cspec ↗
PP2 VCEPNot applicable: ENIGMA BRCA2 explicitly prohibits PP2 because benign missense variation is frequent in the gene. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA2 specification explicitly states that PP2 is not used because BRCA2 has a high frequency of benign missense variants. PP2 is therefore not applicable regardless of the individual missense consequence.

VCEP rule
ENIGMA BRCA2 PP2: Do not use because of the high frequency of benign missense variants.
Evidence considered
  • The ENIGMA BRCA2 specification states: PP2, do not use; high frequency of benign missense variants.
Sources
cspec ↗
PP5 VCEPNot applicable: ENIGMA says do not use PP5, and ClinVar has no exact-variant expert-panel Pathogenic or Likely pathogenic classification. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 V1.2 specification explicitly says PP5 is not for use. Independently, the exact ClinVar record for NM_000059.4:c.6698C>T (p.Ala2233Val) has no expert-panel submission; it has ordinary single-submitter likely-benign laboratory assertions. These assertions cannot trigger PP5, which requires an exact-variant expert-panel Pathogenic or Likely pathogenic classification under the requested rule.

VCEP rule
Do not use.
Evidence considered
  • ENIGMA V1.2 PP5 specification: Do not use.
  • ClinVar exact match NM_000059.4(BRCA2):c.6698C>T (p.Ala2233Val) is Likely benign with zero expert-panel submissions and only single-submitter laboratory assertions; ordinary submissions do not trigger PP5.
Sources
cspec ↗clinvar ↗
BP2 VCEPNot applicable: the ENIGMA BRCA2 VCEP specifies that BP2 must not be used and is restricted to BS2 context. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA2 VCEP specification marks BP2 as do not use and states that it is applied only in the context of BS2; therefore BP2 is not applicable to this adjudication regardless of any possible cis/trans co-observation.

VCEP rule
ENIGMA BRCA2 VCEP Specifications v1.2 BP2: Do not use; applied only in the context of BS2.
Evidence considered
  • ENIGMA BRCA2 VCEP Specifications v1.2 Table 1 states for BP2: 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; specification: do not use; applied only in the context of BS2.
Still missing
  • Specifications_V1.2_2024-11-18.docx was searched for c.6698C>T, p.Ala2233Val, and p.A2233V; no variant-specific entry was found, but the file explicitly designates BP2 as do not use.
Sources
cspec ↗
BP3 VCEPNot applicable: ENIGMA explicitly excludes BP3, and this variant is a missense substitution rather than an in-frame repeat-region indel. Details ▾Hide ▴
Reasoning

BP3 is explicitly designated Not Applicable in the governing ENIGMA BRCA2 V1.2 criteria rules. This variant is missense, not an in-frame deletion or insertion in a repetitive region, so the generic BP3 concept does not apply under the gene-specific framework.

VCEP rule
ENIGMA BRCA2 V1.2 BP3: Not Applicable.
Evidence considered
  • The ENIGMA BRCA2 V1.2 rules list BP3 as Not Applicable.
  • The normalized consequence is missense, NP_000050.3:p.(Ala2233Val), not an in-frame deletion or insertion in a repetitive region.
Still missing
  • No exact entry for c.6698C>T, p.Ala2233Val, or p.A2233V was found when searched in Specifications_V1.2_2024-11-18.docx.txt; the governing rule itself designates BP3 Not Applicable.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
BP6 VCEPNot applicable: ENIGMA says do not use BP6, and ClinVar has no exact-variant expert-panel Benign or Likely benign classification. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 V1.2 specification explicitly says BP6 is not for use. The exact ClinVar record is not an expert-panel classification: it contains only ordinary single-submitter likely-benign laboratory assertions. Under the requested rule, an exact-variant expert-panel Benign or Likely benign classification is required, so these submissions cannot trigger BP6.

VCEP rule
Do not use.
Evidence considered
  • ENIGMA V1.2 BP6 specification: Do not use.
  • ClinVar exact match NM_000059.4(BRCA2):c.6698C>T (p.Ala2233Val) is Likely benign with zero expert-panel submissions and only single-submitter laboratory assertions; ordinary submissions do not trigger BP6.
Sources
cspec ↗clinvar ↗
BP7 N/ANot applicable: p.Ala2233Val is a missense substitution, whereas BP7 is limited to synonymous or qualifying intronic variants. Details ▾Hide ▴
Reasoning

BP7 applies only to synonymous variants or qualifying intronic variants. NM_000059.4:c.6698C>T produces the missense substitution p.Ala2233Val, so BP7 is outside its criterion scope and is not evaluated.

Rule
BP7 is applicable only to synonymous variants or qualifying intronic variants; missense variants are not applicable.
Evidence considered
  • The case identifies NM_000059.4:c.6698C>T as the missense substitution NP_000050.3:p.(Ala2233Val).
  • ENIGMA BRCA2 VCEP Specification v1.2 limits BP7 to synonymous or qualifying intronic variants; this missense variant is outside BP7 scope.
Still missing
  • No variant-specific pre-assigned BP7 entry was found in Specifications_V1.2_2024-11-18.docx.
  • No variant-specific pre-assigned BP7 entry was found in Appendices_V1.2_2024-11-18.docx.
  • No variant-specific pre-assigned BP7 entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.
Sources
cspec ↗

Identifiers

Gene
BRCA2
Transcript
NM_000059.4
Coding (HGVS c.)
NM_000059.4:c.6698C>T
Protein (HGVS p.)
NP_000050.3:p.(Ala2233Val)
GRCh38
chr13:32341053 C>T
GRCh37
chr13:32915190 C>T
Location and type
Exon 11 · missense
ClinVar
409574
COSMIC
COSV66448396

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 -45 bp
0.014
SpliceAI acceptor gainat +83 bp
0.000
SpliceAI donor lossat +143 bp
0.003
SpliceAI donor gainat -131 bp
0.000
Pangolin splice lossmagnitude shown
-0.020
Pangolin splice gain
0.001

Other predictors

REVEL
0.555
BayesDel
0.081

How the predictions were used

PP3 Not met: REVEL 0.555 is below the >=0.644 supporting PP3 threshold and remains in the non-informative gray zone. Details ▾Hide ▴
Reasoning

NM_000059.4:c.6698C>T (p.Ala2233Val) is a missense variant, so the applicable computational path is REVEL only. The REVEL score is 0.555, which is below the ClinGen SVI supporting PP3 threshold of >=0.644 (Pejaver et al. 2022, PMID:36413997) and therefore does not meet PP3. SpliceAI is not used for this missense PP3 decision, although its available maximum delta is 0.014. No variant-specific pre-assigned PP3 code was found in the searched ENIGMA Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, or PMID_22505045_Houdayer_2012_HumMutat.pdf files.

Rule
For a missense variant, evaluate PP3 using REVEL only; supporting PP3 requires REVEL >=0.644. A gray-zone result does not meet PP3 and does not permit substitution of SpliceAI.
Evidence considered
  • The case identifies NM_000059.4:c.6698C>T as the missense substitution NP_000050.3:p.(Ala2233Val).
  • The applicable missense predictor is REVEL; the recorded REVEL score is 0.555.
  • ClinGen SVI REVEL calibration assigns supporting PP3 at REVEL >=0.644 (Pejaver et al. 2022, PMID:36413997); 0.555 does not reach that threshold.
  • SpliceAI max delta 0.014 was not used for missense PP3 because PP3/BP4 evidence must come from the single consequence-matched path.
  • ENIGMA BRCA2 VCEP Specification v1.2 and Appendix J were consulted; no variant-specific pre-assigned PP3 entry was found in the searched governing files.
Still missing
  • No variant-specific pre-assigned PP3 entry was found in Specifications_V1.2_2024-11-18.docx.
  • No variant-specific pre-assigned PP3 entry was found in Appendices_V1.2_2024-11-18.docx.
  • No variant-specific pre-assigned PP3 entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.
Sources
cspec ↗revel
BP4 Not met: REVEL 0.555 exceeds the <=0.29 supporting BP4 threshold and is therefore a gray-zone missense result. Details ▾Hide ▴
Reasoning

NM_000059.4:c.6698C>T (p.Ala2233Val) is a missense variant, so the applicable computational path is REVEL only. The REVEL score is 0.555, which exceeds the supporting BP4 threshold of <=0.29 and lies in the gray zone; therefore BP4 is not met. SpliceAI is not substituted for this missense BP4 decision, although its available maximum delta is 0.014. No variant-specific pre-assigned BP4 code was found in the searched ENIGMA Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, or PMID_22505045_Houdayer_2012_HumMutat.pdf files.

Rule
For a missense variant, evaluate BP4 using REVEL only; supporting BP4 requires REVEL <=0.29. A gray-zone result does not meet BP4 and does not permit substitution of SpliceAI.
Evidence considered
  • The case identifies NM_000059.4:c.6698C>T as the missense substitution NP_000050.3:p.(Ala2233Val).
  • The applicable missense predictor is REVEL; the recorded REVEL score is 0.555.
  • ClinGen SVI REVEL calibration assigns supporting BP4 at REVEL <=0.29 (Pejaver et al. 2022, PMID:36413997); 0.555 exceeds that threshold and is not benign-supportive.
  • SpliceAI max delta 0.014 was not used for missense BP4 because PP3/BP4 evidence must come from the single consequence-matched path.
  • ENIGMA BRCA2 VCEP Specification v1.2 and Appendix J were consulted; no variant-specific pre-assigned BP4 entry was found in the searched governing files.
Still missing
  • No variant-specific pre-assigned BP4 entry was found in Specifications_V1.2_2024-11-18.docx.
  • No variant-specific pre-assigned BP4 entry was found in Appendices_V1.2_2024-11-18.docx.
  • No variant-specific pre-assigned BP4 entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.
Sources
cspec ↗revel
BP7 N/ANot applicable: p.Ala2233Val is a missense substitution, whereas BP7 is limited to synonymous or qualifying intronic variants. Details ▾Hide ▴
Reasoning

BP7 applies only to synonymous variants or qualifying intronic variants. NM_000059.4:c.6698C>T produces the missense substitution p.Ala2233Val, so BP7 is outside its criterion scope and is not evaluated.

Rule
BP7 is applicable only to synonymous variants or qualifying intronic variants; missense variants are not applicable.
Evidence considered
  • The case identifies NM_000059.4:c.6698C>T as the missense substitution NP_000050.3:p.(Ala2233Val).
  • ENIGMA BRCA2 VCEP Specification v1.2 limits BP7 to synonymous or qualifying intronic variants; this missense variant is outside BP7 scope.
Still missing
  • No variant-specific pre-assigned BP7 entry was found in Specifications_V1.2_2024-11-18.docx.
  • No variant-specific pre-assigned BP7 entry was found in Appendices_V1.2_2024-11-18.docx.
  • No variant-specific pre-assigned BP7 entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.555. BayesDel score = 0.0812715.

7 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

  • Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.
    No paper-specific finding is recorded.
    PMID 23918944 ↗
  • Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots".
    Dines JN et al. · 2020
    This paper does not explicitly mention BRCA2 c.6698C>T or p.A2233V. It describes BRCA2 exons 10-11 as a missense coldspot spanning codons 266-2281, which includes residue 2233, with no pathogenic or likely pathogenic missense variants in the analyzed region and an estimated pathogenicity odds ratio below 0.01; this is contextual evidence only because the governing ENIGMA framework does not use PM1.
    Does not name this variant
    PMID 31911673 ↗
    Quoted passage
    BRCA2 exons 10 and 11, which account for ~65% of the coding sequence, have no putative P+LP missense variants

    Results, BRCA2 paragraph; Table 1; Table 2

  • ACOG Practice Bulletin No. 103: Hereditary breast and ovarian cancer syndrome.
    2009
    No paper-specific finding is recorded.
    PMID 19305347 ↗
  • NSGC practice guideline: risk assessment and genetic counseling for hereditary breast and ovarian cancer.
    No paper-specific finding is recorded.
    PMID 23188549 ↗
  • American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers.
    No paper-specific finding is recorded.
    PMID 24493721 ↗
  • ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.
    No paper-specific finding is recorded.
    PMID 25356965 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    No paper-specific finding is recorded.
    PMID 28492532 ↗

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 0.014 Open source ↗
ClinVar 1 Likely benign 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 Likely benign (1 clinical laboratory). (ClinVarID = 409574)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.555. BayesDel score = 0.0812715.

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA2, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV66448396, n = 2 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.