0%
BRCA2c.9934A>GLikely benign
Print report
Variant interpretation report

BRCA2 c.9934A>G, p.(Ile3312Val)

NM_000059.4:c.9934A>G NP_000050.3:p.(Ile3312Val) Missense · exon 27 View identifiers
Classification
Likely benign

Variant description:

No variant summary was recorded for this case.

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

Likely benign.A likely benign 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: 0 Benign evidence criteria: 2
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 2
BP1Strong
BP1 · strong

Met at Strong: residue 3312 is outside ENIGMA domains aa 10-40 and aa 2481-3186, with SpliceAI max delta 0.014 <=0.1.

BP4Supporting
BP4 · supporting

Met at supporting strength: REVEL 0.017 is below the BP4 supporting threshold of 0.29 for missense variants.

Recorded classification: Likely benign

Likely Benign: BP1 (strong) plus BP4 (supporting) satisfy the ENIGMA BRCA2 V1.2 combination rule.

02The sources

Evidence at a glance

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

gnomAD v4.1
gnomAD v2.1
Population frequency
22 / 1,614,244 alleles

gnomAD v4.1: 22 / 1,614,244 alleles. Recorded AF 1.36287e-05. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 1.59194e-05; MAF= 0.00159%, 4/251266 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000163026; MAF= 0.01630%, 1/6134 alleles, homozygotes = 0); grpmax FAF= 7.02e-06.

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
0.017 recorded score

Recorded REVEL score: 0.017. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 →
ClinVar submissions
12 reported laboratory submissions

9 Uncertain significance · 2 Likely benign · 1 Likely Benign. ClinVar API review status: criteria provided, conflicting classifications.

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
No matching record reported

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

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

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

28 criteria with recorded statuses: 2 met · 5 not met · 11 not assessed · 10 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.9934A>G, the governing ENIGMA BRCA2 VCEP framework classifies the consequence as an exonic missense substitution, p.(Ile3312Val).

PVS1, PM4, and BP3 are each not applicable under the VCEP-specific rules because this is neither a null variant nor an in-frame length-changing variant.

PS3 and BS3 were not assessed because the governing ENIGMA functional-assay table contains no entry for this variant and the case evidence contains no variant-specific protein-function assay result.

PS4 was not assessed because the governing VCEP requires exact-variant case-control statistics and the available evidence is a single case observation; the declared ST7 workbook could not be converted and therefore remains an explicit verification gap.

PP4 and BP5 were both evaluated from the exact BRCA2 clinical-history LR row; LR 0.7815407011846 is below the PP4 lower threshold and above the BP5 upper threshold.

PP5 and BP6 were not met because no exact-variant ClinVar expert-panel classification exists; single-submitter laboratory classifications do not qualify.

All four requested criteria remain not_assessed because the governing ENIGMA population rules require non-cancer gnomAD subsets and, for PM2, local depth, while the case bundle supplies only all-comers v2.1/v4.1 summaries.

The available all-comers data do not meet the numerical BA1 or BS1 FAF thresholds, and they show no homozygotes, but those observations cannot replace the governing subset-specific evidence requirements.

Met · 2

BP1 StrongMet at Strong: residue 3312 is outside ENIGMA domains aa 10-40 and aa 2481-3186, with SpliceAI max delta 0.014 <=0.1. Details ▾Hide ▴
Reasoning

ENIGMA BRCA2 V1.2 applies BP1_Strong to missense variants outside a potentially clinically important functional domain when SpliceAI is <=0.1. p.Ile3312Val is at residue 3312, outside the defined BRCA2 PALB2-binding domain aa 10-40 and DNA-binding domain aa 2481-3186, and the case SpliceAI maximum delta is 0.014. Therefore BP1_Strong is met.

Rule
ENIGMA BRCA2 BP1_Strong: missense or in-frame variant outside a potentially clinically important functional domain AND SpliceAI <=0.1.
Evidence considered
  • ENIGMA V1.2 BP1 rule: BP1_Strong applies to missense or in-frame variants outside a potentially clinically important functional domain with no predicted splicing impact (SpliceAI <=0.1).
  • The variant is missense p.Ile3312Val at residue 3312; the governing ENIGMA domains are aa 10-40 and aa 2481-3186, so residue 3312 is outside the domains.
  • SpliceAI max delta is 0.014, below the ENIGMA BP1 threshold of 0.1.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18spliceai ↗
BP4 SupportingMet at supporting strength: REVEL 0.017 is below the BP4 supporting threshold of 0.29 for missense variants. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, p.(Ile3312Val), so the applicable computational path is REVEL rather than SpliceAI. REVEL is 0.017, meeting the published BP4 supporting threshold of <=0.29 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997). The SpliceAI score is not used for this missense BP4 determination. No exact c.9934A>G, p.Ile3312Val, or p.I3312V entry 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
For a missense variant, use the REVEL path only; BP4 supporting requires REVEL <=0.29 under the supplied ClinGen SVI calibration thresholds.
Evidence considered
  • The case normalization identifies NM_000059.4:c.9934A>G as the missense variant NP_000050.3:p.(Ile3312Val), also p.(I3312V).
  • The recorded REVEL score is 0.017.
  • The published ClinGen SVI REVEL calibration assigns BP4 supporting at REVEL <=0.29 (Pejaver et al. 2022, PMID:36413997).
  • The ENIGMA BRCA2 specification governs PP3/BP4/BP7; SpliceAI is not substituted for the applicable missense REVEL path.
Still missing
  • No exact c.9934A>G, p.Ile3312Val, or p.I3312V entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.9934A>G, p.Ile3312Val, or p.I3312V entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.9934A>G, p.Ile3312Val, or p.I3312V entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗revel

Not met · 5 · evaluated, threshold not reached

PP3 Not met: REVEL 0.017 is below the PP3 supporting threshold of 0.644 for missense variants. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, p.(Ile3312Val), so the applicable computational path is REVEL rather than SpliceAI. REVEL is 0.017, below the published PP3 supporting threshold of 0.644 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997), so PP3 is not met. No exact c.9934A>G, p.Ile3312Val, or p.I3312V entry 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
For a missense variant, use the REVEL path only; PP3 supporting requires REVEL >=0.644 under the supplied ClinGen SVI calibration thresholds.
Evidence considered
  • The case normalization identifies NM_000059.4:c.9934A>G as the missense variant NP_000050.3:p.(Ile3312Val), also p.(I3312V).
  • The recorded REVEL score is 0.017.
  • The published ClinGen SVI REVEL calibration assigns PP3 supporting at REVEL >=0.644 (Pejaver et al. 2022, PMID:36413997).
  • The ENIGMA BRCA2 specification governs PP3/BP4/BP7 and identifies the relevant BRCA2 functional domains and splice-prediction rules.
Still missing
  • No exact c.9934A>G, p.Ile3312Val, or p.I3312V entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.9934A>G, p.Ile3312Val, or p.I3312V entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.9934A>G, p.Ile3312Val, or p.I3312V entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗revel
PP4 Not met: exact-variant clinical-history LR 0.7815407011846 >= 2.08? no, so it does not reach the ENIGMA PP4 Supporting threshold. Details ▾Hide ▴
Reasoning

The ENIGMA specification requires PP4 to capture only combined multifactorial clinical likelihood evidence and states the Supporting operator as LR >=2.08:1. The exact BRCA2 clinical-history table entry for c.9934A>G gives log LR -0.2464880496263504 and LR 0.7815407011846. Explicit comparison: 0.7815407011846 >= 2.08? no. The value is in the non-informative zone, so PP4 is not met.

Rule
PP4 Supporting: LR >=2.08:1; Moderate >=4.3:1; Strong >=18.7:1; Very Strong >=350:1.
Evidence considered
  • ENIGMA BRCA2 v1.2 specifies PP4 Supporting as combined multifactorial clinical LR >=2.08:1; stronger levels use >=4.3, >=18.7, and >=350.
  • The exact BRCA2 c.9934A>G table row reports LR 0.7815407011846 (log LR -0.2464880496263504; one observation). Explicit comparison: 0.7815407011846 >= 2.08? no.
Sources
cspec ↗vcep_pmid_31853058_brca2_clinical_history_lrPMID:31853058 ↗
PP5 Not met: ClinVar has zero exact-variant expert-panel submissions, and no expert-panel Pathogenic or Likely pathogenic classification is present. Details ▾Hide ▴
Reasoning

The exact ClinVar record has no expert-panel submission: the audit reports zero expert-panel submissions, and the available classifications are single-submitter Uncertain significance or Likely benign. Under the required rule, PP5 may be applied only when an exact-variant ClinVar expert panel classifies the variant as Pathogenic or Likely pathogenic. That condition is absent, so PP5 is not met; ordinary laboratory submissions and aggregate labels are excluded.

Rule
PP5 applies only to an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification.
Evidence considered
  • The exact ClinVar record reports zero expert-panel submissions; available submissions are single-submitter Uncertain significance or Likely benign classifications.
  • PP5 was restricted to an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification; none is present.
Sources
clinvar ↗
BP5 Not met: exact-variant clinical-history LR 0.7815407011846 <= 0.48? no, so it does not reach the ENIGMA BP5 Supporting threshold. Details ▾Hide ▴
Reasoning

The ENIGMA specification states the BP5 Supporting operator as LR <=0.48:1 and restricts BP5 to combined multifactorial likelihood clinical data. The exact BRCA2 clinical-history table entry for c.9934A>G gives LR 0.7815407011846. Explicit comparison using BP5's own direction: 0.7815407011846 <= 0.48? no. Therefore BP5 is not met; the LR is also in the non-informative interval above 0.48 and below 1.00.

Rule
BP5 Supporting: LR <=0.48:1; Moderate <=0.23:1; Strong <=0.05:1; Very Strong <=0.00285:1.
Evidence considered
  • ENIGMA BRCA2 v1.2 specifies BP5 Supporting as combined multifactorial clinical LR <=0.48:1, with Moderate <=0.23, Strong <=0.05, and Very Strong <=0.00285.
  • The exact BRCA2 c.9934A>G table row reports LR 0.7815407011846. Explicit comparison: 0.7815407011846 <= 0.48? no.
Sources
cspec ↗vcep_pmid_31853058_brca2_clinical_history_lrPMID:31853058 ↗
BP6 Not met: ClinVar has zero exact-variant expert-panel submissions, so no expert-panel Benign or Likely benign classification supports BP6. Details ▾Hide ▴
Reasoning

The exact ClinVar record has no expert-panel submission: the audit reports zero expert-panel submissions. The available exact-variant classifications are single-submitter Uncertain significance or Likely benign, not an expert-panel Benign or Likely benign assertion. Under the required rule, BP6 may be applied only for an exact-variant ClinVar expert-panel Benign or Likely benign classification; therefore BP6 is not met.

Rule
BP6 applies only to an exact-variant ClinVar expert-panel Benign or Likely benign classification.
Evidence considered
  • The exact ClinVar record reports zero expert-panel submissions; its Likely benign classifications are from individual clinical laboratories.
  • BP6 was restricted to an exact-variant ClinVar expert-panel Benign or Likely benign classification; none is present.
Sources
clinvar ↗

Not assessed · 11 · no assessment recorded

PS1 Not assessed: no governing-VCEP entry or established pathogenic comparator for p.Ile3312Val was identified in the searched files. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, and ENIGMA specifies PS1 when the same amino-acid substitution has previously been established as pathogenic, with no confirmed or predicted splicing effect. The governing VCEP searches found no entry for c.9934A>G, p.Ile3312Val, or p.I3312V 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. The exact-variant literature report describes p.Ile3312Val as a VUS but does not establish a pathogenic same-amino-acid comparator; therefore PS1 cannot be assigned from the available evidence.

Rule
ENIGMA PS1: same amino-acid change as a previously established pathogenic variant regardless of nucleotide change; missense protein-change application requires no confirmed or predicted mRNA splicing effect (SpliceAI <=0.1).
Evidence considered
  • ENIGMA V1.2 states that PS1 applies to a missense substitution with the same amino-acid change as a previously established pathogenic variant; for protein-change application, SpliceAI must be <=0.1.
  • The case is NM_000059.4:c.9934A>G, NP_000050.3:p.(Ile3312Val)/p.(I3312V), with SpliceAI max delta 0.014, satisfying the no-predicted-splicing-impact prerequisite but not supplying the required pathogenic comparator.
  • PMID:33773534 reports the exact c.9934A>G p.(Ile3312Val) variant in a germline sequencing cohort and labels it VUS; it does not provide an established pathogenic same-amino-acid comparator.
Still missing
  • No entry for c.9934A>G, p.Ile3312Val, or p.I3312V was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.9934A>G, p.Ile3312Val, or p.I3312V was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No entry for c.9934A>G, p.Ile3312Val, or p.I3312V was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • A curated pathogenic or likely pathogenic BRCA2 variant producing the same p.Ile3312Val amino-acid change was not established.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18PMID:33773534 ↗
PS3 Not assessed: no variant-specific protein-function assay or pre-assigned PS3 code was found in the governing ENIGMA materials. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 VCEP specification reserves PS3 for well-established protein-function assays or combined mRNA-and-protein assays and directs calibrated variant-specific assignments to Specifications_Table9_V1.2_2024-11-18.xlsx. Exact searches for c.9934A>G, p.Ile3312Val, and p.I3312V found no entry 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. The case literature extraction reports this variant from germline sequencing as a VUS but provides no functional assay result. Therefore, no validated damaging functional evidence is available to assess PS3.

Rule
ENIGMA BRCA2 PS3: apply for well-established in vitro or in vivo studies supportive of a damaging effect measured via protein only or mRNA and protein combined; use calibrated Table 9 assignments when present.
Evidence considered
  • The ENIGMA specification states that PS3 applies to well-established functional assays measuring protein function alone or mRNA and protein together, with calibrated assignments in Table 9.
  • Exact searches for c.9934A>G, p.Ile3312Val, and p.I3312V found no variant entry 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.
  • The extracted PMID:33773534 report lists BRCA2 c.9934A>G p.(Ile3312Val) from germline sequencing and classifies it as a VUS, but reports no protein-function assay result.
Still missing
  • No c.9934A>G, p.Ile3312Val, or p.I3312V entry was found in Specifications_Table9_V1.2_2024-11-18.xlsx.
  • No c.9934A>G, p.Ile3312Val, or p.I3312V entry was found in Specifications_V1.2_2024-11-18.docx.
  • No c.9934A>G, p.Ile3312Val, or p.I3312V entry was found in Appendices_V1.2_2024-11-18.docx.
  • No c.9934A>G, p.Ile3312Val, or p.I3312V entry was found in HUMU-40-1557-s001.xlsx.
  • No validated variant-specific damaging protein-function assay result was identified in the case evidence.
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_humu_40_1557_s001PMID:33773534 ↗
PS4 Not assessed: no exact-variant case-control odds ratio, p-value, and confidence interval were available for PS4 (p-value <=0.05 and OR >=4). Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA2 specification states for PS4: "Case-control studies; p-value <=0.05 and OR >=4 (lower confidence interval excludes 2.0)." No exact-variant case-control p-value, odds ratio, or confidence interval was identified. PMID:33773534 reports one affected individual with c.9934A>G, p.(Ile3312Val), but a single case observation is not the specified case-control evidence. The governing SupplementaryTables_V1.2_2024-11-18.xlsx was searched for c.9934A>G, p.Ile3312Val, and p.I3312V, but its full text is unavailable because the workbook could not be converted; therefore its ST7 posterior/LR entry cannot be verified. The required inequality is OR >=4, but no OR value is available for substitution.

Rule
PS4: case-control p-value <=0.05 AND OR >=4, with lower confidence interval excluding 2.0.
Evidence considered
  • ENIGMA BRCA2 v1.2 specifies PS4 for case-control studies with p-value <=0.05, OR >=4, and a lower confidence interval excluding 2.0.
  • PMID:33773534 reports the exact variant in one 71-year-old patient with high-grade serous neoplasm and classifies it as a VUS; this is not a case-control estimate.
  • The declared SupplementaryTables_V1.2_2024-11-18.xlsx could not be converted to searchable full text, so its ST7 Reference Set entry could not be checked.
Still missing
  • No exact-variant case-control odds ratio, p-value, or confidence interval was identified.
  • SupplementaryTables_V1.2_2024-11-18.xlsx full text is unavailable because conversion failed; ST7 could not be searched or verified.
Sources
cspec ↗vcep_supplementarytables_v1_2_2024_11_18PMID:33773534 ↗
PM2 Not assessed: required non-cancer absence and depth data are unavailable; all-comers gnomAD reports 4/251266 alleles in v2.1 and 22/1614244 in v4.1. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 specification permits PM2 Supporting only when the variant is absent from controls in an outbred population in gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, with average local read depth at least 25. The variant is present in the available all-comers gnomAD v2.1 record at 4/251266 alleles (AF 1.59194e-05) and in v4.1 at 22/1614244 alleles (AF 1.36287e-05), but the required non-cancer subset allele counts and depth are not provided. Therefore PM2 cannot be formally adjudicated.

Rule
ENIGMA BRCA2 PM2 Supporting: absent from controls in gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, with average read depth >=25.
Evidence considered
  • The ENIGMA BRCA2 specification requires absence from gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, with average read depth >=25, for PM2 Supporting.
  • The available all-comers gnomAD v2.1 record reports 4/251266 alleles, AF 1.59194e-05, and 0 homozygotes.
  • The available all-comers gnomAD v4.1 record reports 22/1614244 alleles, AF 1.36287e-05, and 0 homozygotes; this does not establish absence in the governing non-cancer datasets.
Still missing
  • The case evidence does not provide GNOMAD_V2_1_NON_CANCER exome or GNOMAD_V3_1_NON_CANCER genome allele counts for the variant.
  • The required average read depth of at least 25 around the variant is not reported for the governing non-cancer datasets.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18gnomad_v2 ↗gnomad_v4 ↗
PM3 Not assessed: the exact-variant report documents heterozygosity but no Fanconi-anemia phenotype, second pathogenic BRCA2 variant, or phase needed for ENIGMA PM3 points. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP specification restricts PM3 to patients with a phenotype consistent with BRCA1/2-related Fanconi anemia who carry the assessed variant with a pathogenic or likely pathogenic variant in the same gene, with point assignment based on phase and the number and severity of qualifying observations. The available exact-variant publication reports a heterozygous BRCA2 c.9934A>G (p.Ile3312Val) finding in a 71-year-old patient with high-grade serous neoplasm, but reports no Fanconi-anemia phenotype, second pathogenic BRCA2 variant, phase, or affected-proband allelic observation sufficient for PM3. Therefore PM3 cannot be assigned from the available evidence.

Rule
ENIGMA BRCA2 PM3_VariableWeight: apply only for a patient with a phenotype consistent with BRCA1/2-related Fanconi anemia and co-occurring variants in the same gene; PM3_Supporting = 1 point, PM3 = 2 points, PM3_Strong = 4 or more points.
Evidence considered
  • The ENIGMA BRCA2 VCEP specification states that PM3 applies to a patient with a phenotype consistent with BRCA1- or BRCA2-related Fanconi anemia and a co-occurring pathogenic or likely pathogenic variant in the same gene; PM3 strength is based on Table 6 points, with 1 point for supporting, 2 for moderate, and 4 or more for strong evidence.
  • The exact-variant report lists BRCA2 c.9934A>G (p.Ile3312Val) in a 71-year-old patient with high-grade serous neoplasm, heterozygous variant allele frequency 0.47, and no reported second BRCA2 pathogenic variant or phase information.
  • The case evidence does not document Fanconi-anemia chromosome-breakage findings or the required qualifying clinical features for the ENIGMA PM3 phenotype gate.
Still missing
  • No entry for c.9934A>G, p.Ile3312Val, or p.I3312V was found when searched in Specifications_V1.2_2024-11-18.docx.txt; the file provides the governing PM3 rule but no variant-specific PM3 assignment.
  • No qualifying Fanconi-anemia phenotype, pathogenic or likely pathogenic BRCA2 variant in the same patient, phase determination, or additional affected-proband PM3 observation is documented in the reviewed case evidence.
Sources
cspec ↗PMID:33773534 ↗
PP1 Not assessed: no segregation LR or tested affected relatives were reported, so the ENIGMA PP1 threshold of LR >=2.08 cannot be evaluated. Details ▾Hide ▴
Reasoning

No quantitative co-segregation likelihood ratio, affected-relative genotype results, pedigree meioses, or other family-level segregation dataset was identified for BRCA2 c.9934A>G (p.Ile3312Val). The ENIGMA specification requires quantitative co-segregation evidence 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; none can be assigned without an observed LR or equivalent analyzable family data. PMID:33773534 reports one affected individual carrying the variant and a sister with thyroid cancer, but does not report testing of the sister or segregation of the variant in the family.

Rule
PP1_VariableWeight: apply only from quantitative co-segregation analysis; Supporting LR >=2.08, Moderate LR >=4.3, Strong LR >=18.7, Very Strong LR >=350.
Evidence considered
  • ENIGMA BRCA2 Specification v1.2 requires quantitative co-segregation analysis for PP1 and sets thresholds of LR >=2.08 for Supporting, LR >=4.3 for Moderate, LR >=18.7 for Strong, and LR >=350 for Very Strong.
  • The exact variant c.9934A>G (p.Ile3312Val) is reported in PMID:33773534 in one 71-year-old patient; the table also lists a sister with thyroid cancer, but provides no genotype or segregation result for that relative.
  • No case-level pedigree, parental testing, affected-relative testing, meiosis count, or quantitative segregation LR was found in the reviewed case evidence.
Still missing
  • No quantitative co-segregation likelihood ratio or Bayes score was available for this variant.
  • No affected-relative genotypes, pedigree meioses, or documented parental/offspring segregation results were available.
  • PMID:33773534 reports one carrier and a sister with thyroid cancer, but does not report genotype testing or segregation in that family.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18PMID:33773534 ↗
BA1 Not assessed: required non-cancer FAF data are unavailable; available all-comers group-max FAF values were 7.02e-06 and 8.78e-06 versus the >0.001 BA1 threshold. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 specification requires filter allele frequency above 0.001 (0.1%) in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes. The available case evidence reports only all-comers gnomAD v2.1 and v4.1 values; their group-max FAF values are 7.02e-06 and 8.78e-06, respectively, both below 0.001, but the required non-cancer subset result is not available. Therefore BA1 cannot be adjudicated from the governing population source.

Rule
ENIGMA BRCA2 BA1: FAF >0.001 in gnomAD v2.1 non-cancer exome-only and/or gnomAD v3.1 non-cancer non-founder populations.
Evidence considered
  • The ENIGMA BRCA2 specification sets BA1 at filter allele frequency >0.001 (0.1%) in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes.
  • The available all-comers gnomAD v2.1 record reports group-max FAF 7.02e-06, with 4/251266 alleles and 0 homozygotes.
  • The available all-comers gnomAD v4.1 record reports group-max FAF 8.78e-06, with 22/1614244 alleles and 0 homozygotes; gnomAD v4.1 is not the governing older non-cancer source for this criterion.
Still missing
  • The case evidence does not provide GNOMAD_V2_1_NON_CANCER exome or GNOMAD_V3_1_NON_CANCER genome filter allele frequency for NM_000059.4:c.9934A>G; the governing ENIGMA specification requires those sources.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18gnomad_v2 ↗gnomad_v4 ↗
BS1 Not assessed: required non-cancer FAF data are unavailable; available all-comers group-max FAF values were 7.02e-06 and 8.78e-06 versus the >0.00002 BS1 threshold. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 specification assigns BS1 Strong when FAF is >0.0001 and BS1 Supporting when FAF is >0.00002 to <=0.0001 in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes. Only all-comers values are available: group-max FAF 7.02e-06 in v2.1 and 8.78e-06 in v4.1, both below 0.00002. Because the required non-cancer source data are missing, BS1 cannot be formally adjudicated.

Rule
ENIGMA BRCA2 BS1: Strong for FAF >0.0001; Supporting for FAF >0.00002 and <=0.0001, using gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes.
Evidence considered
  • The ENIGMA BRCA2 specification sets BS1 Strong at FAF >0.0001 and BS1 Supporting at FAF >0.00002 to <=0.0001 in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes.
  • The available all-comers gnomAD v2.1 record reports group-max FAF 7.02e-06, below the lowest BS1 threshold.
  • The available all-comers gnomAD v4.1 record reports group-max FAF 8.78e-06, below the lowest BS1 threshold and not the specified v3.1 non-cancer source.
Still missing
  • The case evidence does not provide GNOMAD_V2_1_NON_CANCER exome or GNOMAD_V3_1_NON_CANCER genome filter allele frequency for NM_000059.4:c.9934A>G; the governing ENIGMA specification requires those sources.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18gnomad_v2 ↗gnomad_v4 ↗
BS2 Not assessed: gnomAD reports 0 homozygotes, but no phenotype-qualified biallelic observations or ENIGMA BS2 point assignments are available. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 specification applies BS2 to phenotype-qualified observations of the variant in trans with a pathogenic or likely pathogenic BRCA2 variant, or as a homozygote, in individuals unlikely to have Fanconi anemia; point totals determine strength. The available gnomAD records show zero homozygotes, but provide no qualifying clinical cohort observations, phase information, age or follow-up, Fanconi anemia assessment, or BS2 point assignments. The specification also states that gnomAD homozygote observations are not to be used for BS2 frequency evidence. Thus BS2 is not assessable from the available evidence.

Rule
ENIGMA BRCA2 BS2: apply only for qualifying unaffected or unlikely-Fanconi-anemia individuals with a homozygote or trans co-occurrence; assign Supporting at 1 point, Moderate at 2 points, and Strong at 4 or more points.
Evidence considered
  • The ENIGMA BRCA2 BS2 rule requires phenotype-qualified biallelic evidence and assigns strength from cumulative points: BS2 at 4 or more points, BS2 Moderate at 2 points, and BS2 Supporting at 1 point.
  • The ENIGMA appendix explicitly states that BS2 scoring is not to be applied to gnomAD frequency data; observations of at least two gnomAD homozygotes are instead captured by BA1 or BS1.
  • The available gnomAD v2.1 and v4.1 records each report 0 homozygotes, without the clinical information needed for BS2 scoring.
Still missing
  • No qualifying clinical or research-cohort observations of c.9934A>G in trans with a pathogenic or likely pathogenic BRCA2 variant or as a homozygote were provided.
  • No age, follow-up, Fanconi anemia phenotype assessment, phase information, or ENIGMA BS2 point assignment was provided.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18gnomad_v2 ↗gnomad_v4 ↗
BS3 Not assessed: no variant-specific protein-function assay or pre-assigned BS3 code was found in the governing ENIGMA materials. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 VCEP specification reserves BS3 for well-established protein-function assays or combined mRNA-and-protein assays showing no damaging effect and directs calibrated variant-specific assignments to Specifications_Table9_V1.2_2024-11-18.xlsx. Exact searches for c.9934A>G, p.Ile3312Val, and p.I3312V found no entry 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. The case literature extraction reports this variant from germline sequencing as a VUS but provides no functional assay result. Therefore, no validated benign functional evidence is available to assess BS3.

Rule
ENIGMA BRCA2 BS3: apply for well-established in vitro or in vivo studies showing no damaging effect measured via protein only or mRNA and protein combined; use calibrated Table 9 assignments when present.
Evidence considered
  • The ENIGMA specification states that BS3 applies to well-established functional assays showing no damaging effect measured via protein only or mRNA and protein together, with calibrated assignments in Table 9.
  • Exact searches for c.9934A>G, p.Ile3312Val, and p.I3312V found no variant entry 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.
  • The extracted PMID:33773534 report lists BRCA2 c.9934A>G p.(Ile3312Val) from germline sequencing and classifies it as a VUS, but reports no protein-function assay result.
Still missing
  • No c.9934A>G, p.Ile3312Val, or p.I3312V entry was found in Specifications_Table9_V1.2_2024-11-18.xlsx.
  • No c.9934A>G, p.Ile3312Val, or p.I3312V entry was found in Specifications_V1.2_2024-11-18.docx.
  • No c.9934A>G, p.Ile3312Val, or p.I3312V entry was found in Appendices_V1.2_2024-11-18.docx.
  • No c.9934A>G, p.Ile3312Val, or p.I3312V entry was found in HUMU-40-1557-s001.xlsx.
  • No validated variant-specific benign protein-function assay result was identified in the case evidence.
Sources
cspec ↗vcep_specifications_table9_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_humu_40_1557_s001PMID:33773534 ↗
BS4 Not assessed: no non-segregation LR or tested discordant affected relatives were reported, so the ENIGMA BS4 threshold of LR <=0.48 cannot be evaluated. Details ▾Hide ▴
Reasoning

No quantitative lack-of-segregation likelihood ratio, affected-relative genotype discordance, pedigree meioses, or other family-level non-segregation dataset was identified for BRCA2 c.9934A>G (p.Ile3312Val). The ENIGMA specification requires quantitative co-segregation analysis and assigns BS4 Supporting at LR <=0.48, BS4 Moderate at LR <=0.23, BS4 Strong at LR <=0.05, and BS4 Very Strong at LR <=0.00285; none can be assigned without an observed LR or equivalent analyzable family data. PMID:33773534 reports one affected carrier and a sister with thyroid cancer but does not report testing of the sister or non-segregation.

Rule
BS4_VariableWeight: apply only from quantitative lack-of-segregation analysis; Supporting LR <=0.48, Moderate LR <=0.23, Strong LR <=0.05, Very Strong LR <=0.00285.
Evidence considered
  • ENIGMA BRCA2 Specification v1.2 requires quantitative co-segregation analysis for BS4 and sets thresholds of LR <=0.48 for Supporting, LR <=0.23 for Moderate, LR <=0.05 for Strong, and LR <=0.00285 for Very Strong.
  • The exact variant c.9934A>G (p.Ile3312Val) is reported in PMID:33773534 in one 71-year-old patient; the table also lists a sister with thyroid cancer, but provides no genotype or non-segregation result for that relative.
  • No case-level pedigree, parental testing, affected-relative testing, meiosis count, or quantitative non-segregation LR was found in the reviewed case evidence.
  • The VCEP-indexed SupplementaryTables_V1.2.xlsx could not be converted to searchable full text, so it remains an unresolved lookup gap for BS4.
Still missing
  • No quantitative lack-of-segregation likelihood ratio or Bayes score was available for this variant.
  • No affected-relative genotypes, pedigree meioses, or documented discordant family segregation results were available.
  • PMID:33773534 reports one carrier and a sister with thyroid cancer, but does not report genotype testing or non-segregation in that family.
  • SupplementaryTables_V1.2.xlsx was declared by the VCEP index for BS4/PS4, but its full text was unavailable for conversion; this is a file-access gap, not evidence that the variant is absent from the table.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18PMID:33773534 ↗
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: c.9934A>G is missense p.(Ile3312Val), not a VCEP-defined null variant eligible for PVS1. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA2 VCEP framework applies PVS1 to null variants such as nonsense, frameshift, canonical ±1,2 splice-site, initiation-codon, or exon deletion/duplication variants. NM_000059.4:c.9934A>G is an exonic missense variant, NP_000050.3:p.(Ile3312Val), so it does not enter the BRCA2 PVS1 decision tree. The VCEP specification, appendices, and Table 4 were searched for c.9934A>G, p.Ile3312Val, and p.I3312V; no variant-specific entry was found. The case evidence independently identifies the consequence as missense, with no evidence of a truncating consequence, NMD-triggering transcript, or altered protein length.

Rule
ENIGMA BRCA2 V1.2 PVS1 applies to defined null variants through the BRCA2 PVS1 decision tree; an exonic missense variant is outside scope.
Evidence considered
  • ENIGMA BRCA2 V1.2 Table 1 defines PVS1 for null variants and directs application through the VCEP PVS1 flowchart and Table 4.
  • ENIGMA BRCA2 V1.2 Appendix D states that PVS1 is assigned only after triage of predicted loss-of-function variants through the BRCA2 decision tree.
  • The consolidated case evidence identifies NM_000059.4:c.9934A>G as missense, encoding NP_000050.3:p.(Ile3312Val), with no truncation or NMD-triggering consequence.
  • The four governing VCEP text files were searched under c.9934A>G, p.Ile3312Val, and p.I3312V; no variant-specific entry was found.
Still missing
  • No c.9934A>G, p.Ile3312Val, or p.I3312V entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No c.9934A>G, p.Ile3312Val, or p.I3312V entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No c.9934A>G, p.Ile3312Val, or p.I3312V entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • No c.9934A>G, p.Ile3312Val, or p.I3312V entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_specifications_table4_v1_2_2024_11_18
PS2 VCEPNot applicable: ENIGMA explicitly prohibits PS2 for BRCA2 because de novo cancer occurrences lack calibrated predictive value. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP specification explicitly states that PS2 is not to be used because BRCA1/2-related cancers are relatively common and the predictive capacity of de novo occurrences has not been calibrated. Therefore, the criterion is not applicable regardless of whether parental testing is available.

VCEP rule
PS2: Do not use under the ENIGMA BRCA2 VCEP specification.
Evidence considered
  • ENIGMA BRCA2 Specification v1.2 Table 1 states for PS2: 'Do not use'; the stated reason is that BRCA1/2-related cancers occur relatively commonly and there is no information to calibrate the predictive capacity of de novo occurrences.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PM1 VCEPNot applicable: residue 3312 lies outside ENIGMA's BRCA2 critical domains aa 10-40 and aa 2481-3186, and PM1 is explicitly N/A. Details ▾Hide ▴
Reasoning

ENIGMA BRCA2 V1.2 explicitly marks PM1 as not applicable for BRCA2 missense interpretation and directs domain evidence to BP1, BP4, and PP3. Its defined clinically important domains include BRCA2 PALB2 binding aa 10-40 and DNA binding aa 2481-3186; residue 3312 is outside both domains. vcep_materials.json has no domain_tables entry for BRCA2, so the complete governing VCEP domain definition is the applicable authority.

VCEP rule
ENIGMA BRCA2 PM1: Not Applicable; clinically important domains are evaluated through BP1, BP4, and PP3 rather than PM1.
Evidence considered
  • ENIGMA V1.2 Appendix J/Table 16 marks PM1 as not applicable for BRCA1/2 missense interpretation and states that domain information is captured under BP1, BP4, and PP3.
  • The ENIGMA domain definition used for BRCA2 identifies the PALB2-binding domain at aa 10-40 and the DNA-binding domain at aa 2481-3186; p.Ile3312Val is at residue 3312 and is outside both.
  • The case vcep_materials.json domain_tables object is empty, so no additional gene-specific domain table supersedes the complete ENIGMA domain definition.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18
PM4 VCEPNot applicable: p.(Ile3312Val) is a single-amino-acid substitution with no in-frame length change or stop-loss consequence. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA2 VCEP explicitly states that PM4 is not used and is considered within the bioinformatic PP3/BP4 analysis. Its PM4 definition is limited to protein-length changes from in-frame insertions/deletions in a non-repeat region or stop-loss variants. NM_000059.4:c.9934A>G is a single-nucleotide missense substitution, p.(Ile3312Val), with no insertion, deletion, stop-loss, or protein-length change. The VCEP specification, appendices, and Table 4 were searched for all three variant notations without a variant-specific entry.

VCEP rule
ENIGMA BRCA2 V1.2 PM4 is not used; this missense SNV does not produce an in-frame length change or stop-loss protein consequence.
Evidence considered
  • ENIGMA BRCA2 V1.2 Table 1 defines PM4 as protein-length change from an in-frame insertion/deletion in a non-repeat region or a stop-loss variant, and says PM4 is not used.
  • The consolidated case evidence identifies a missense SNV producing p.(Ile3312Val), with no protein-length change or stop-loss consequence.
  • The four governing VCEP text files were searched under c.9934A>G, p.Ile3312Val, and p.I3312V; no variant-specific entry was found.
Still missing
  • No c.9934A>G, p.Ile3312Val, or p.I3312V entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No c.9934A>G, p.Ile3312Val, or p.I3312V entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No c.9934A>G, p.Ile3312Val, or p.I3312V entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • No c.9934A>G, p.Ile3312Val, or p.I3312V entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_specifications_table4_v1_2_2024_11_18
PM5 N/ANot applicable: p.Ile3312Val is missense, whereas ENIGMA PM5 is restricted to protein-termination-codon variants. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA2 specification restricts PM5 to protein-termination-codon variants in an exon where a different proven pathogenic protein-termination variant has been observed, with strength assigned by the exon-level Table 4. This variant is missense, c.9934A>G p.Ile3312Val, not a PTC; Table 4 therefore does not apply. The searched Table 4 file contains no entry for c.9934A>G, p.Ile3312Val, or p.I3312V.

Rule
ENIGMA PM5: apply only to genomic PTC changes in an exon where a different proven pathogenic PTC variant has been observed; use Table 4 for exon-specific PM5_PTC strength.
Evidence considered
  • ENIGMA V1.2 defines PM5 only for a protein-termination-codon variant in an exon with a different proven pathogenic PTC variant, and refers to Table 4 for the applicable PTC strength.
  • The case consequence is missense and the protein change is p.Ile3312Val, so the PTC-specific PM5 rule is not applicable.
Still missing
  • No entry for c.9934A>G, p.Ile3312Val, or p.I3312V was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt; this is expected because the VCEP PM5 rule is PTC-specific.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_specifications_table4_v1_2_2024_11_18
PM6 VCEPNot applicable: ENIGMA explicitly prohibits PM6 because uncalibrated de novo occurrences do not provide usable BRCA2 evidence. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 VCEP specification explicitly states that PM6 is not to be used because BRCA1/2-related cancers are relatively common and the predictive capacity of de novo occurrences has not been calibrated. Therefore, the criterion is not applicable even without confirmation of paternity or maternity.

VCEP rule
PM6: Do not use under the ENIGMA BRCA2 VCEP specification.
Evidence considered
  • ENIGMA BRCA2 Specification v1.2 Table 1 states for PM6: 'Do not use'; the stated reason is that BRCA1/2-related cancers occur relatively commonly and there is no information to calibrate the predictive capacity of de novo occurrences.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PP2 VCEPNot applicable: the governing ENIGMA BRCA2 V1.2 criterion table explicitly marks PP2 as not applicable. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA2 V1.2 criterion table explicitly marks PP2 as Not Applicable. No generic PP2 inference is used because the governing VCEP framework takes precedence.

VCEP rule
ENIGMA BRCA2 PP2: Not Applicable.
Evidence considered
  • The ENIGMA BRCA2 V1.2 structured criterion rules list PP2 with applicability Not Applicable.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
BP2 VCEPNot applicable: ENIGMA explicitly excludes BP2 for BRCA2 and permits it only in the context of BS2. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA2 VCEP specification explicitly designates BP2 as not applicable and states that it is applied only in the context of BS2. BP2 therefore cannot be assigned for this variant, regardless of whether a cis or trans observation might otherwise be considered under generic ACMG/AMP wording.

VCEP rule
ENIGMA BRCA2 BP2: do not use; applied only in the context of BS2.
Evidence considered
  • The ENIGMA BRCA2 VCEP specification lists BP2 as 'Do not use' and states that it is applied only in the context of BS2.
Still missing
  • No entry for c.9934A>G, p.Ile3312Val, or p.I3312V was found when searched in Specifications_V1.2_2024-11-18.docx.txt; the file's governing BP2 rule is a criterion-level exclusion rather than a variant-specific row.
Sources
cspec ↗
BP3 VCEPNot applicable: c.9934A>G is a missense SNV, not an in-frame insertion or deletion in a repetitive region. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA2 VCEP explicitly states that BP3 is not used and is captured by bioinformatic prediction and domain analysis. BP3 is defined for in-frame deletions or insertions in a repetitive region without a known function. NM_000059.4:c.9934A>G is a missense SNV encoding p.(Ile3312Val), not an in-frame insertion or deletion, so repeat-region context cannot make BP3 applicable. The VCEP specification, appendices, and Table 4 were searched for all three variant notations without a variant-specific entry.

VCEP rule
ENIGMA BRCA2 V1.2 BP3 is not used; BP3 applies only to in-frame insertion/deletion variants in repetitive regions without known function.
Evidence considered
  • ENIGMA BRCA2 V1.2 Table 1 defines BP3 for in-frame deletions or insertions in repetitive regions without known function and says BP3 is not used.
  • The consolidated case evidence identifies a missense SNV producing p.(Ile3312Val), not an in-frame insertion or deletion.
  • The four governing VCEP text files were searched under c.9934A>G, p.Ile3312Val, and p.I3312V; no variant-specific entry was found.
Still missing
  • No c.9934A>G, p.Ile3312Val, or p.I3312V entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No c.9934A>G, p.Ile3312Val, or p.I3312V entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No c.9934A>G, p.Ile3312Val, or p.I3312V entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • No c.9934A>G, p.Ile3312Val, or p.I3312V entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_specifications_table4_v1_2_2024_11_18
BP7 N/ANot applicable: c.9934A>G is missense, whereas BP7 applies only to synonymous variants. Details ▾Hide ▴
Reasoning

BP7 applies only to synonymous variants. NM_000059.4:c.9934A>G is a missense substitution producing p.(Ile3312Val), so BP7 is outside its criterion scope and no predictor evaluation is applicable.

Rule
BP7 is applicable only to synonymous variants; missense variants are not evaluated under BP7.
Evidence considered
  • The case normalization classifies NM_000059.4:c.9934A>G as missense with protein consequence p.(Ile3312Val).
  • The ENIGMA BRCA2 specification limits BP7 to silent/synonymous variants and certain intronic variants.
Sources
cspec ↗

Identifiers

Gene
BRCA2
Transcript
NM_000059.4
Coding (HGVS c.)
NM_000059.4:c.9934A>G
Protein (HGVS p.)
NP_000050.3:p.(Ile3312Val)
GRCh38
chr13:32398447 A>G
GRCh37
chr13:32972584 A>G
Location and type
Exon 27 · missense
ClinVar
4802369, 38265

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 22 / 1,614,244 alleles AF 1.36e-05 · 0 homozygotes · FAF 8.78e-06
gnomAD v2.1 4 / 251,266 alleles AF 1.59e-05 · 0 homozygotes · FAF 7.02e-06
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.4e-05 · 22 / 1,614,244 alleles · 0 hom · FAF 8.8e-06
Remaining individuals2 / 62,512 3.2e-05
East Asian1 / 44,890 2.2e-05
South Asian2 / 91,086 2.2e-05
European (non-Finnish)17 / 1,180,044 1.4e-05
0 alternate alleles recorded in 6 other groups: Admixed American, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 1.6e-05 · 4 / 251,266 alleles · 0 hom · FAF 7e-06
Remaining individuals1 / 6,134 0.00016
European (non-Finnish)3 / 113,608 2.6e-05
0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.36287e-05; MAF= 0.00136%, 22/1614244 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 3.19939e-05; MAF= 0.00320%, 2/62512 alleles, homozygotes = 0); grpmax FAF= 8.78e-06.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 1.59194e-05; MAF= 0.00159%, 4/251266 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000163026; MAF= 0.01630%, 1/6134 alleles, homozygotes = 0); grpmax FAF= 7.02e-06.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +139 bp
0.009
SpliceAI acceptor gainat -309 bp
0.014
SpliceAI donor lossat -88 bp
0.000
SpliceAI donor gainat -1 bp
0.000
Pangolin splice lossmagnitude shown
-0.015
Pangolin splice gain
0.009

Other predictors

REVEL
0.017
BayesDel
-0.721

How the predictions were used

BP4 SupportingMet at supporting strength: REVEL 0.017 is below the BP4 supporting threshold of 0.29 for missense variants. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, p.(Ile3312Val), so the applicable computational path is REVEL rather than SpliceAI. REVEL is 0.017, meeting the published BP4 supporting threshold of <=0.29 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997). The SpliceAI score is not used for this missense BP4 determination. No exact c.9934A>G, p.Ile3312Val, or p.I3312V entry 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
For a missense variant, use the REVEL path only; BP4 supporting requires REVEL <=0.29 under the supplied ClinGen SVI calibration thresholds.
Evidence considered
  • The case normalization identifies NM_000059.4:c.9934A>G as the missense variant NP_000050.3:p.(Ile3312Val), also p.(I3312V).
  • The recorded REVEL score is 0.017.
  • The published ClinGen SVI REVEL calibration assigns BP4 supporting at REVEL <=0.29 (Pejaver et al. 2022, PMID:36413997).
  • The ENIGMA BRCA2 specification governs PP3/BP4/BP7; SpliceAI is not substituted for the applicable missense REVEL path.
Still missing
  • No exact c.9934A>G, p.Ile3312Val, or p.I3312V entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.9934A>G, p.Ile3312Val, or p.I3312V entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.9934A>G, p.Ile3312Val, or p.I3312V entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗revel
PP3 Not met: REVEL 0.017 is below the PP3 supporting threshold of 0.644 for missense variants. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, p.(Ile3312Val), so the applicable computational path is REVEL rather than SpliceAI. REVEL is 0.017, below the published PP3 supporting threshold of 0.644 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997), so PP3 is not met. No exact c.9934A>G, p.Ile3312Val, or p.I3312V entry 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
For a missense variant, use the REVEL path only; PP3 supporting requires REVEL >=0.644 under the supplied ClinGen SVI calibration thresholds.
Evidence considered
  • The case normalization identifies NM_000059.4:c.9934A>G as the missense variant NP_000050.3:p.(Ile3312Val), also p.(I3312V).
  • The recorded REVEL score is 0.017.
  • The published ClinGen SVI REVEL calibration assigns PP3 supporting at REVEL >=0.644 (Pejaver et al. 2022, PMID:36413997).
  • The ENIGMA BRCA2 specification governs PP3/BP4/BP7 and identifies the relevant BRCA2 functional domains and splice-prediction rules.
Still missing
  • No exact c.9934A>G, p.Ile3312Val, or p.I3312V entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.9934A>G, p.Ile3312Val, or p.I3312V entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.9934A>G, p.Ile3312Val, or p.I3312V entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗revel
BP7 N/ANot applicable: c.9934A>G is missense, whereas BP7 applies only to synonymous variants. Details ▾Hide ▴
Reasoning

BP7 applies only to synonymous variants. NM_000059.4:c.9934A>G is a missense substitution producing p.(Ile3312Val), so BP7 is outside its criterion scope and no predictor evaluation is applicable.

Rule
BP7 is applicable only to synonymous variants; missense variants are not evaluated under BP7.
Evidence considered
  • The case normalization classifies NM_000059.4:c.9934A>G as missense with protein consequence p.(Ile3312Val).
  • The ENIGMA BRCA2 specification limits BP7 to silent/synonymous variants and certain intronic variants.
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.017. BayesDel score = -0.72086.

8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Recorded publications

  • Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.
    No paper-specific finding is recorded.
    PMID 23918944 ↗
  • An integrated in silico approach to analyze the involvement of single amino acid polymorphisms in FANCD1/BRCA2-PALB2 and FANCD1/BRCA2-RAD51 complex.
    Doss CG et al. · 2014
    No paper-specific finding is recorded.
    PMID 24817641 ↗
  • Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
    No paper-specific finding is recorded.
    PMID 25741868 ↗
  • BRCA1 and BRCA2 sequence variations detected with next-generation sequencing in patients with premature ovarian insufficiency.
    Yılmaz NK et al. · 2016
    No paper-specific finding is recorded.
    PMID 27403073 ↗
  • Validation and optimization of the Ion Torrent S5 XL sequencer and Oncomine workflow for BRCA1 and BRCA2 genetic testing.
    No paper-specific finding is recorded.
    PMID 28422718 ↗
  • Next Generation Sequencing-Based Germline Panel Testing for Breast and Ovarian Cancers in Pakistan.
    This paper reports BRCA2 c.9934A>G, p.(Ile3312Val) as a heterozygous germline missense variant in a patient with high-grade serous neoplasm and classifies it as a variant of uncertain significance; it does not provide evidence of truncation, NMD, protein-length change, or an in-frame repeat-region indel.
    Names this variant
    PMID 33773534 ↗
    Quoted passage
    71 BRCA2 Missense c.9934A>G p.(Ile3312Val) Global= 0.00001592, SA= 0.00 Heterozygous (0.47) VUS High grade serous neoplasm Thyroid cancer (Sister)

    Results, Table 1, BRCA2 variants

  • The&#xa0;relationship between mutation carriage of&#xa0;BRCA1/2 and clinicopathological characteristics in women with breast cancer - experience from a&#xa0;diagnostic centre in Turkey.
    No paper-specific finding is recorded.
    PMID 39451174 ↗
  • American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.
    No paper-specific finding is recorded.
    PMID 17392385 ↗

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

gnomAD v4.1 22 / 1,614,244 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.014 Open source ↗
ClinVar 9 Uncertain significance · 2 Likely benign · 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

This variant is present in gnomAD v4.1 (AF= 1.36287e-05; MAF= 0.00136%, 22/1614244 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 3.19939e-05; MAF= 0.00320%, 2/62512 alleles, homozygotes = 0); grpmax FAF= 8.78e-06.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 1.59194e-05; MAF= 0.00159%, 4/251266 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000163026; MAF= 0.01630%, 1/6134 alleles, homozygotes = 0); grpmax FAF= 7.02e-06.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (9 clinical laboratories) and as Likely benign (2 clinical laboratories) and as Likely Benign (1 clinical laboratory). (ClinVarID = 38265)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.017. BayesDel score = -0.72086.

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 not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.