Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
This variantScenario
BenignPathogenic
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
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About BRCA1
BRCA1 encodes a large nuclear protein that helps maintain genomic stability by coordinating the repair of DNA double-strand breaks through homologous recombination, and it also regulates transcription and the cell cycle. It acts as a tumor suppressor, working with proteins such as RAD51, BRCA2, BARD1, and PALB2 to preserve genome integrity. Inherited alterations in BRCA1 cause hereditary breast and ovarian cancer syndrome, with elevated risks of breast, ovarian, prostate, and pancreatic cancers, and biallelic loss underlies a rare form of Fanconi anemia. Because BRCA1-driven tumors rely on impaired DNA repair, they are treatable with PARP inhibitors.
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 BRCA1 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.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA1, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
ACMG/AMP criteria under ClinGen BRCA1 VCEP v1.2, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 1 not met · 14 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
All three requested criteria are not applicable under the ENIGMA BRCA1 VCEP specification because the variant is a missense substitution and the governing PM4 and BP3 rows explicitly say not to use those criteria.
No paper was relevant to PVS1, PM4, or BP3 for this variant, so paper_findings is empty.
For this missense variant, ENIGMA excludes PM1, PM5, and PP2; PS1 cannot be assessed without a qualifying same-protein pathogenic or likely pathogenic reference variant; BP1_Strong is met from domain location and SpliceAI.
The variant p.Ala1082Val lies outside all ENIGMA-defined BRCA1 critical or potentially critical functional domains, and its SpliceAI maximum delta is 0.008.
Within the requested phenotype/prevalence group, PS4 and PP4/BP5 remain not assessed because the required variant-specific case-control or combined multifactorial LR evidence is unavailable.
PP5 and BP6 are not applicable because the ENIGMA VCEP explicitly says not to use them.
PP3 is not met because the VCEP splice threshold is SpliceAI ≥0.2 and the observed maximum delta is 0.008; the protein-impact PP3 path is limited to variants inside a clinically important domain.
BP4 is not applicable because the VCEP missense BP4 path is limited to variants inside a clinically important domain, and this variant is outside all listed BRCA1 domains.
BP7 is not assessed because the variant is in scope for BP7_Strong (RNA), but no qualifying mRNA-only assay result is available.
No population criterion is assigned because the case evidence lacks the VCEP-required frequency/depth quality fields for BA1, BS1, and PM2, and lacks the clinical point data required for BS2.
The four governing VCEP full-text files were searched for c.3245C>T, p.Ala1082Val, and p.A1082V; no exact variant entry was found in any of them.
No criteria match.
Met · 1
BP1StrongVCEPMet at Strong: Ala1082 is outside ENIGMA domains and SpliceAI maximum delta is 0.008, below the ≤0.1 no-splicing threshold.
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Reasoning
The ENIGMA BP1_Strong rule applies to missense variants outside a potentially clinically important functional domain when no splicing is predicted. Ala1082 is outside the VCEP-defined BRCA1 RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857 domains. SpliceAI maximum delta is 0.008, meeting the VCEP no-splicing condition of ≤0.1. The rule also states that missense prediction is not applicable on this path, so no BayesDel threshold is used.
VCEP rule
Apply BP1_Strong for silent substitution, missense or in-frame insertion, deletion or delins variants outside a (potentially) clinically important functional domain
AND
no splicing predicted (SpliceAI ≤0.1).
Missense prediction not applicable.
Evidence considered
Specifications V1.2 Table 1, BP1_Strong: applies to silent, missense, or in-frame insertion/deletion/delins variants outside a potentially clinically important functional domain with SpliceAI ≤0.1; missense prediction is not applicable.
Appendix J/Table 16 lists the applicable BRCA1 domains as RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857; p.Ala1082Val is outside these ranges.
SpliceAI case result: maximum delta score 0.008 (DS_AG 0.008, DS_AL 0.000, DS_DG 0.000, DS_DL 0.001).
PP3VCEPNot met: SpliceAI maximum delta 0.008 is below the VCEP PP3 splice threshold of ≥0.2, and the variant is outside the domain required for the protein-impact path.
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Reasoning
The variant is missense p.(Ala1082Val) and lies outside the VCEP-defined BRCA1 clinically important domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT repeats aa 1650-1857), so the PP3 protein-impact path does not apply. The VCEP separately permits PP3 for predicted splicing in missense variants irrespective of domain location, requiring SpliceAI ≥0.2. The case SpliceAI maximum delta score is 0.008, below that threshold, so the splice path is not met. BayesDel no-AF is -0.0316675, but it is not usable for the PP3 protein path because the variant is outside the required domain; it also does not meet the VCEP BRCA1 protein-impact threshold of ≥0.28. No governing VCEP table entry for c.3245C>T, p.Ala1082Val, or p.A1082V was found in the searched supplementary or full-text VCEP files.
VCEP rule
Apply PP3 for missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain and predicted impact via protein change (BayesDel predicted Impact). ... Apply PP3 for predicted splicing (SpliceAI ≥0.2) for silent, missense/in-frame (irrespective of location in clinically important functional domain) and for intronic variants outside of the donor and acceptor ±1,2 positions.
Evidence considered
The VCEP PP3 rule applies to missense or in-frame variants inside a potentially clinically important functional domain when BayesDel no-AF predicts protein impact, and separately applies to predicted splicing with SpliceAI ≥0.2 for missense variants irrespective of domain location.
For BRCA1, the VCEP defines protein-impact PP3 at BayesDel no-AF ≥0.28; the observed BayesDel no-AF score is -0.0316675, but the missense is outside the required clinically important domain.
SpliceAI results for NM_007294.4:c.3245C>T are DS_AG 0.008, DS_AL 0.0, DS_DG 0.0, and DS_DL 0.001; maximum delta score 0.008, below the VCEP PP3 threshold.
The VCEP-defined BRCA1 domains are RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857; p.Ala1082Val is outside all three.
SupplementaryTables_V1.2_2024-11-18.xlsx.txt was searched for c.3245C>T, p.Ala1082Val, and p.A1082V; no matching row was found.
Still missing
No variant-specific entry was found after searching SupplementaryTables_V1.2_2024-11-18.xlsx.txt for c.3245C>T, p.Ala1082Val, and p.A1082V.
No variant-specific entry was found after searching Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, and PMID_22505045_Houdayer_2012_HumMutat.pdf.txt for c.3245C>T, p.Ala1082Val, and p.A1082V.
PS1VCEPNot assessed: SpliceAI is 0.008, but no qualifying pathogenic or likely pathogenic alternate nucleotide change producing p.Ala1082Val was identified.
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Reasoning
The ENIGMA PS1 rule requires a different nucleotide change producing the same missense substitution as a known pathogenic or likely pathogenic variant, with no confirmed or predicted splicing effect. The case evidence contains no qualifying pathogenic or likely pathogenic BRCA1 variant producing p.Ala1082Val, and searches of Specifications_Table4_V1.2_2024-11-18.xlsx, SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_V1.2_2024-11-18.docx, and Appendices_V1.2_2024-11-18.docx found no entry for c.3245C>T, p.Ala1082Val, or p.A1082V. The available SpliceAI maximum delta score is 0.008, but without a qualifying reference variant PS1 cannot be assigned.
VCEP rule
Apply PS1, for predicted missense substitutions, where a previously classified pathogenic variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)). ... Apply PS1_Moderate, for predicted missense substitutions, where previously established likely pathogenic variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1)).
Evidence considered
Variant normalization: NM_007294.4:c.3245C>T produces NP_009225.1:p.(Ala1082Val), also p.(A1082V).
The four governing VCEP full-text files named for this case were searched for c.3245C>T, p.Ala1082Val, p.A1082V, and residue 1082; no qualifying alternate-nucleotide same-protein reference variant was found.
Still missing
A VCEP-qualified pathogenic or likely pathogenic BRCA1 alternate nucleotide change producing p.Ala1082Val is needed to assess PS1.
No entry for c.3245C>T, p.Ala1082Val, or p.A1082V was found in Specifications_Table4_V1.2_2024-11-18.xlsx, SupplementaryTables_V1.2_2024-11-18.xlsx, Specifications_V1.2_2024-11-18.docx, or Appendices_V1.2_2024-11-18.docx.
PS3VCEPNot assessed: no variant-specific calibrated protein or combined mRNA/protein assay result or pre-assigned PS3 code was found for c.3245C>T.
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Reasoning
The ENIGMA BRCA1 VCEP reserves PS3 for well-established functional studies showing a damaging effect, measured through protein alone or combined mRNA and protein assays. The governing Table 9 contains no row for c.3245C>T, p.Ala1082Val, or p.A1082V, and the supplementary functional-assay dataset and Parsons multifactorial supplement also contain no matching variant entry. The case's fetched functional-theme papers were checked through their extracted findings; none mentions this variant or supplies variant-specific functional assay data. Therefore, the available evidence does not permit application of PS3 at any strength; absence of a matching table row is recorded as a search gap rather than evidence of a benign or damaging functional effect.
VCEP rule
Well-established in vitro or in vivo functional studies supportive of a damaging effect. Apply PS3 for assays measuring effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.
Evidence considered
ENIGMA BRCA1 VCEP Specifications Table 9, searched for c.3245C>T, p.Ala1082Val, and p.A1082V: no matching row found; Table 9 is the VCEP table for calibrated PS3/BS3 recommendations.
ENIGMA BRCA1 VCEP Supplementary Tables, searched for c.3245C>T, p.Ala1082Val, and p.A1082V: no matching functional-assay dataset entry found.
Parsons et al. 2019 Supplementary Table 1, searched for c.3245C>T, p.Ala1082Val, and p.A1082V: no matching variant row found.
PMID:25230021 paper extract: the variant was not mentioned and no variant-specific functional result was reported.
PMID:31911673 paper extract: the variant was not explicitly mentioned and no variant-specific functional assay result was reported.
Still missing
No matching c.3245C>T, p.Ala1082Val, or p.A1082V entry was found in Specifications_Table9_V1.2_2024-11-18.xlsx.txt.
No matching c.3245C>T, p.Ala1082Val, or p.A1082V entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt, including the functional assay dataset.
No matching c.3245C>T, p.Ala1082Val, or p.A1082V entry was found in HUMU-40-1557-s001.xlsx.txt.
The extracted findings for PMID:25230021 and PMID:31911673 do not mention this variant or provide variant-specific functional assay results.
PS4VCEPNot assessed: no variant-specific case-control p-value, OR, or confidence interval is available to evaluate p-value ≤0.05 and OR ≥4 with a lower CI excluding 2.0.
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Reasoning
The ENIGMA rule requires case-control evidence with p-value ≤0.05, OR ≥4, and a lower confidence interval excluding 2.0. The available case evidence contains no variant-specific case-control counts, odds ratio, confidence interval, or p-value for NM_007294.4:c.3245C>T (p.Ala1082Val/p.A1082V). The ClinVar record is a conflicting/single-submitter record and does not supply the required case-control dataset. PS4 therefore cannot be evaluated without substituting evidence not permitted by the VCEP.
VCEP rule
The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls. ... Case-control studies; p-value ≤0.05 and OR ≥4 (lower confidence interval excludes 2.0).
Evidence considered
ENIGMA BRCA1/2 Specifications v1.2, PS4 rule: case-control studies require p-value ≤0.05 and OR ≥4, with the lower confidence interval excluding 2.0.
ClinVar exact variant record NM_007294.4(BRCA1):c.3245C>T (p.Ala1082Val) reports conflicting classifications and no case-control p-value, odds ratio, or confidence interval.
Direct searches of the governing VCEP full-text files for c.3245C>T, p.Ala1082Val, and p.A1082V found no variant-specific entry.
Still missing
No variant-specific case-control dataset with p-value, odds ratio, and confidence interval was available for NM_007294.4:c.3245C>T.
The VCEP Specifications_V1.2_2024-11-18.docx.txt was searched for c.3245C>T, p.Ala1082Val, and p.A1082V; no variant-level entry was found.
PM2VCEPNot assessed: the variant is absent from both specified non-cancer gnomAD datasets, but required average read depth (>=25) is not reported.
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Reasoning
The ENIGMA PM2 Supporting rule requires absence from controls in an outbred population in gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, with average read depth at least 25 around the variant. The case evidence reports the variant absent from both non-cancer datasets, but provides no average read-depth value, no quality-control result, and no underlying frequency record; therefore the PM2 read-depth requirement cannot be evaluated. The variant was searched under c.3245C>T, p.Ala1082Val, and p.A1082V in SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, and HUMU-40-1557-s001.xlsx.txt, with no exact entry found.
VCEP rule
Absent from controls in an outbred population, from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer). Region around the variant must have an average read depth ≥25. See Appendix G for details.
Evidence considered
The case gnomAD results report the variant absent from gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer; both records have empty source_data objects and do not provide average depth or QC values.
ENIGMA Specifications Table 1 defines PM2 Supporting as absence from the specified non-cancer gnomAD controls with average read depth at least 25 around the variant.
ENIGMA Appendix G recommends read depth above 25 for PM2 Supporting and exclusion of data when the variant failed quality control.
The four governing VCEP full-text files named for this interpretation were searched for c.3245C>T, p.Ala1082Val, and p.A1082V; no exact variant row was found.
Still missing
The case evidence provides no average read-depth value around the variant.
The case evidence provides no quality-control result or underlying non-cancer gnomAD frequency record.
No exact variant entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
No exact variant entry was found in Specifications_V1.2_2024-11-18.docx.txt.
No exact variant entry was found in Appendices_V1.2_2024-11-18.docx.txt.
No exact variant entry was found in HUMU-40-1557-s001.xlsx.txt.
PM3VCEPNot assessed: no documented co-occurring BRCA1 pathogenic variant, phase information, or qualifying Fanconi Anemia phenotype is available.
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Reasoning
PM3 cannot be assessed from the available evidence. The ENIGMA rule requires a patient with a phenotype consistent with BRCA1-related Fanconi Anemia and a co-occurrent variant in the same gene, with point assignment based on the phase of the co-occurrent pathogenic or likely pathogenic variant and the Fanconi Anemia phenotype. The case evidence bundle contains no documented co-occurring pathogenic or likely pathogenic BRCA1 variant, phase information, affected-proband observation, chromosome-breakage result, or qualifying Fanconi Anemia clinical features. Searches of the governing full-text VCEP directory found no entry for c.3245C>T, p.Ala1082Val, or p.A1082V in Specifications_V1.2_2024-11-18.docx.txt.
VCEP rule
Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene. See Table 6 for approach to assign points per proband, and final PM3 code assignment based on the sum of PM3-related points.
Evidence considered
ENIGMA Specifications V1.2, PM3 rule and Table 6: PM3 requires a same-gene co-occurring pathogenic or likely pathogenic variant in a patient with a qualifying BRCA1-related Fanconi Anemia phenotype, and assigns points according to phase and phenotype.
The case evidence bundle provides no case-specific co-occurrence, phase, affected-proband, chromosome-breakage, or qualifying Fanconi Anemia phenotype evidence for NM_007294.4:c.3245C>T.
The governing full-text VCEP directory was searched for c.3245C>T, p.Ala1082Val, and p.A1082V; no matching entry was found in Specifications_V1.2_2024-11-18.docx.txt.
Still missing
No documented co-occurring pathogenic or likely pathogenic BRCA1 variant for this case.
No phase evidence establishing trans, cis, homozygous, or unknown phase for a co-occurring variant.
No affected-proband Fanconi Anemia phenotype or chromosome-breakage result meeting the VCEP rule.
No entry for c.3245C>T, p.Ala1082Val, or p.A1082V was found when Specifications_V1.2_2024-11-18.docx.txt was searched; the governing full-text VCEP directory was searched for all three notations.
PP1VCEPNot assessed: no quantitative co-segregation likelihood ratio or documented informative affected-family meioses is available for this variant.
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Reasoning
PP1 cannot be assessed because the available case evidence does not provide a quantitative co-segregation analysis, likelihood ratio, informative meioses, or sufficiently documented affected-family segregation for NM_007294.4:c.3245C>T (p.Ala1082Val). The governing VCEP rule requires co-segregation in multiple affected family members measured by a quantitative method and assigns strength by LR; no such value is available.
VCEP rule
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease, as measured by a quantitative co-segregation analysis method. See Appendix I for details. ... Apply weight as per Bayes Score: ... PP1 - LR ≥2.08:1 ... PP1_Moderate – LR≥4.3:1 ... PP1_Strong – LR≥18.7:1 ... PP1_Very Strong – LR≥350:1
Evidence considered
Case evidence contains no quantitative co-segregation LR, family-level segregation table, affected/unaffected relative genotype data, or meiosis count for NM_007294.4:c.3245C>T (p.Ala1082Val).
The variant was searched in the governing ENIGMA specification full text and in HUMU-40-1557-s001.xlsx.txt under c.3245C>T, p.Ala1082Val, and p.A1082V; no variant-specific row was found.
Still missing
No quantitative co-segregation result or LR was available for NM_007294.4:c.3245C>T (p.Ala1082Val).
No variant-specific entry was found in Specifications_V1.2_2024-11-18.docx.txt, the governing ENIGMA specification full text, for this variant.
No variant-specific entry was found in HUMU-40-1557-s001.xlsx.txt, the ENIGMA multifactorial likelihood supplementary file, for this variant.
PP4VCEPNot assessed: no combined multifactorial clinical LR is available for comparison with the PP4 supporting threshold of LR ≥2.08:1.
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Reasoning
ENIGMA PP4 is restricted to combined multifactorial clinical likelihood evidence and requires a combined LR toward pathogenicity. The Li et al. BRCA1 clinical-history LR table was searched for exact Gene=BRCA1 and c.3245C>T; no row for this variant was found, and no other combined clinical LR was available. Therefore the PP4 threshold cannot be evaluated.
VCEP rule
Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data. ... PP4 - LR ≥2.08:1 ... Combined LR 1.00 to <2.08 is not informative (PP4 not applicable).
Evidence considered
ENIGMA PP4 is for combined LR toward pathogenicity from multifactorial clinical data; the supporting threshold is PP4 - LR ≥2.08:1.
Li et al. 2020 BRCA1 clinical-history LR Supplementary Table 3 was searched for exact Gene=BRCA1 and c.3245C>T, with alternate protein notations p.Ala1082Val and p.A1082V; no matching row was found.
Easton et al. 2007 was listed as methodology/context for multifactorial likelihood analysis, but no variant-specific combined LR for c.3245C>T was available.
Still missing
No combined multifactorial clinical likelihood ratio was available for this variant.
PMID_31853058_BRCA1_clinical_history_LR.xlsx.txt was searched for c.3245C>T, p.Ala1082Val, p.A1082V, and 3245; no matching row was found.
The VCEP Specifications_V1.2_2024-11-18.docx.txt was searched for c.3245C>T, p.Ala1082Val, and p.A1082V; no variant-level entry was found.
BA1VCEPNot assessed: gnomAD non-cancer records are absent, but the required BA1 FAF threshold (>0.001) and read-depth quality gate are not reported.
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Reasoning
The ENIGMA rule requires FAF >0.001 in the specified non-cancer, non-founder gnomAD populations, with read depth not below 20. The case evidence records the variant as absent from gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer, but provides no FAF value, read-depth value, or quality-control result; therefore the BA1 threshold and required quality gate cannot be evaluated. The variant was searched under c.3245C>T, p.Ala1082Val, and p.A1082V in SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, and HUMU-40-1557-s001.xlsx.txt, with no exact entry found.
VCEP rule
Filter allele frequency (FAF) is above 0.1% (FAF > 0.001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.
Evidence considered
The case gnomAD results report the variant absent from gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer; both records have empty source_data objects and do not provide FAF, depth, or QC values.
ENIGMA Specifications Table 1 states that BA1 uses gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, based on maximum filter allele frequency in non-founder populations considered separately, and excludes application when read depth is below 20.
ENIGMA Appendix G states that BA1/BS1 use filter allele frequency, the highest value in a non-founder gnomAD population, with exome and genome data assessed separately.
The four governing VCEP full-text files named for this interpretation were searched for c.3245C>T, p.Ala1082Val, and p.A1082V; no exact variant row was found.
Still missing
The case evidence provides no non-cancer gnomAD FAF value for the variant.
The case evidence provides no read-depth value or quality-control result for the relevant gnomAD records.
No exact variant entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
No exact variant entry was found in Specifications_V1.2_2024-11-18.docx.txt.
No exact variant entry was found in Appendices_V1.2_2024-11-18.docx.txt.
No exact variant entry was found in HUMU-40-1557-s001.xlsx.txt.
BS1VCEPNot assessed: gnomAD non-cancer records are absent, but the required BS1 FAF thresholds (>0.00002) and read-depth quality gate are not reported.
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Reasoning
The ENIGMA rule requires FAF >0.0001 for BS1 Strong or FAF >0.00002 and <=0.0001 for BS1 Supporting in the specified non-cancer, non-founder gnomAD populations, with read depth not below 20. The case evidence records the variant as absent from gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer, but provides no FAF value, read-depth value, or quality-control result; therefore the applicable BS1 threshold and required quality gate cannot be evaluated. The variant was searched under c.3245C>T, p.Ala1082Val, and p.A1082V in SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, and HUMU-40-1557-s001.xlsx.txt, with no exact entry found.
VCEP rule
Filter allele frequency (FAF) is above 0.01% (FAF > 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details. ... Filter allele frequency (FAF) is above 0.002% (FAF > 0.00002) and less than or equal to 0.01% (FAF ≤ 0.0001) in gnomAD v2.1 (non-cancer, exome only subset) and/or gnomAD v3.1 (non-cancer), non-founder population(s). See Appendix G for details.
Evidence considered
The case gnomAD results report the variant absent from gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer; both records have empty source_data objects and do not provide FAF, depth, or QC values.
ENIGMA Specifications Table 1 assigns BS1 Strong above 0.0001 and BS1 Supporting above 0.00002 through 0.0001, using gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes in separate analyses, and excludes application when read depth is below 20.
ENIGMA Appendix G states that BA1/BS1 use filter allele frequency, the highest value in a non-founder gnomAD population, with exome and genome data assessed separately.
The four governing VCEP full-text files named for this interpretation were searched for c.3245C>T, p.Ala1082Val, and p.A1082V; no exact variant row was found.
Still missing
The case evidence provides no non-cancer gnomAD FAF value for the variant.
The case evidence provides no read-depth value or quality-control result for the relevant gnomAD records.
No exact variant entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
No exact variant entry was found in Specifications_V1.2_2024-11-18.docx.txt.
No exact variant entry was found in Appendices_V1.2_2024-11-18.docx.txt.
No exact variant entry was found in HUMU-40-1557-s001.xlsx.txt.
BS2VCEPNot assessed: no qualifying healthy-adult, zygosity, Fanconi Anemia, follow-up, or BS2 point data are available.
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Reasoning
The ENIGMA BS2 rule requires healthy-adult observations relevant to the inheritance context, absence of Fanconi Anemia features, and point assignment from the specified clinical or research cohort presentations. The available case evidence contains no healthy-adult observation, zygosity or phase information, Fanconi Anemia phenotype assessment, cancer age/follow-up, or BS2 points. The VCEP explicitly excludes homozygote observations from gnomAD data from BS2 point assignment because frequency-based codes capture those observations. Therefore BS2 cannot be assessed.
VCEP rule
Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. See Specifications Table 8 for additional stipulations, and approach to assign points per proband, and final BS2 code assignment based on the sum of BS2-related points. See Appendix H for additional details.
Evidence considered
ENIGMA Specifications Table 1 defines BS2 as applied in the absence of Fanconi Anemia features and directs point assignment by the BS2-related table.
ENIGMA Specifications Table 8 assigns points by clinical presentation, including age at first cancer or cancer-unaffected follow-up, and states that gnomAD homozygote observations are not to be used for BS2 because frequency-based codes capture them.
The case bundle contains no variant-specific BS2 clinical observation or point data.
Still missing
No qualifying clinical or research cohort observation of this variant in a healthy adult is available.
No zygosity, phase, Fanconi Anemia phenotype, cancer-age, or follow-up data are available.
No BS2-related points can be assigned from the available evidence.
BS3VCEPNot assessed: no variant-specific calibrated benign protein or combined mRNA/protein assay result or pre-assigned BS3 code was found for c.3245C>T.
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Reasoning
The ENIGMA BRCA1 VCEP reserves BS3 for well-established functional studies showing no damaging effect on protein function, measured through protein alone or combined mRNA and protein assays. The governing Table 9 contains no row for c.3245C>T, p.Ala1082Val, or p.A1082V, and the supplementary functional-assay dataset and Parsons multifactorial supplement also contain no matching variant entry. The case's fetched functional-theme papers were checked through their extracted findings; none mentions this variant or supplies variant-specific benign functional assay data. Therefore, the available evidence does not permit application of BS3 at any strength; absence of a matching table row is recorded as a search gap rather than evidence of a benign functional effect.
VCEP rule
Well-established in vitro or in vivo functional studies shows no damaging effect on protein function. Apply BS3 for assays measuring effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.
Evidence considered
ENIGMA BRCA1 VCEP Specifications Table 9, searched for c.3245C>T, p.Ala1082Val, and p.A1082V: no matching row found; Table 9 is the VCEP table for calibrated PS3/BS3 recommendations.
ENIGMA BRCA1 VCEP Supplementary Tables, searched for c.3245C>T, p.Ala1082Val, and p.A1082V: no matching functional-assay dataset entry found.
Parsons et al. 2019 Supplementary Table 1, searched for c.3245C>T, p.Ala1082Val, and p.A1082V: no matching variant row found.
PMID:25230021 paper extract: the variant was not mentioned and no variant-specific functional result was reported.
PMID:31911673 paper extract: the variant was not explicitly mentioned and no variant-specific functional assay result was reported.
Still missing
No matching c.3245C>T, p.Ala1082Val, or p.A1082V entry was found in Specifications_Table9_V1.2_2024-11-18.xlsx.txt.
No matching c.3245C>T, p.Ala1082Val, or p.A1082V entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt, including the functional assay dataset.
No matching c.3245C>T, p.Ala1082Val, or p.A1082V entry was found in HUMU-40-1557-s001.xlsx.txt.
The extracted findings for PMID:25230021 and PMID:31911673 do not mention this variant or provide variant-specific benign functional assay results.
BS4VCEPNot assessed: no quantitative non-segregation likelihood ratio or documented affected-family discordance is available for this variant.
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Reasoning
BS4 cannot be assessed because the available case evidence does not provide a quantitative co-segregation analysis, likelihood ratio, informative meioses, or sufficiently documented non-segregation in affected family members for NM_007294.4:c.3245C>T (p.Ala1082Val). The governing VCEP rule requires lack of segregation measured by a quantitative method and assigns strength by LR; no such value is available.
VCEP rule
Lack of segregation in affected members of a family, as measured by a quantitative co-segregation analysis method. See Appendix I for details. ... Apply weight as per Bayes Score: ... BS4_Supporting - LR ≤0.48 to >0.23:1 ... BS4_Moderate - LR ≤0.23:1 ... BS4 - LR ≤0.05:1 ... BS4_Very strong – LR ≤0.00285:1
Evidence considered
Case evidence contains no quantitative non-segregation LR, family-level segregation table, affected relative genotype discordance, or meiosis count for NM_007294.4:c.3245C>T (p.Ala1082Val).
The variant was searched in the governing ENIGMA specification full text and in HUMU-40-1557-s001.xlsx.txt under c.3245C>T, p.Ala1082Val, and p.A1082V; no variant-specific row was found.
Still missing
No quantitative non-segregation result or LR was available for NM_007294.4:c.3245C>T (p.Ala1082Val).
No variant-specific entry was found in Specifications_V1.2_2024-11-18.docx.txt, the governing ENIGMA specification full text, for this variant.
No variant-specific entry was found in HUMU-40-1557-s001.xlsx.txt, the ENIGMA multifactorial likelihood supplementary file, for this variant.
BP5VCEPNot assessed: no combined clinical LR is available for the governing BP5 comparison LR ≤0.48, so the benign-supporting threshold cannot be tested.
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Reasoning
ENIGMA BP5 is restricted to combined multifactorial clinical likelihood evidence against pathogenicity. The governing supporting operator is LR ≤0.48, but no combined clinical LR was available for this variant; the Li et al. BRCA1 clinical-history table contained no matching c.3245C>T row. BP5 cannot be assessed without inventing or substituting a clinical LR.
VCEP rule
N/A for co-observation: cases with pathogenic variants in two (or more) different known breast–ovarian cancer risk genes have no specific phenotype. ... Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data. ... BP5 - LR ≤0.48 to >0.23:1
Evidence considered
ENIGMA BP5 is for combined LR against pathogenicity from multifactorial clinical data; the supporting threshold is BP5 - LR ≤0.48 to >0.23:1.
Explicit inequality required by the governing rule: LR ≤0.48; no variant-specific LR is available, so a substituted numeric inequality cannot be written and no BP5 status can be assigned.
Li et al. 2020 BRCA1 clinical-history LR Supplementary Table 3 was searched for exact Gene=BRCA1 and c.3245C>T, with alternate protein notations p.Ala1082Val and p.A1082V; no matching row was found.
Easton et al. 2007 was listed as methodology/context for multifactorial likelihood analysis, but no variant-specific combined LR for c.3245C>T was available.
Still missing
No combined multifactorial clinical likelihood ratio was available for this variant.
PMID_31853058_BRCA1_clinical_history_LR.xlsx.txt was searched for c.3245C>T, p.Ala1082Val, p.A1082V, and 3245; no matching row was found.
The VCEP Specifications_V1.2_2024-11-18.docx.txt was searched for c.3245C>T, p.Ala1082Val, and p.A1082V; no variant-level entry was found.
BP7VCEPNot assessed: The variant is eligible for BP7_Strong (RNA), but no qualifying mRNA-only assay result is available; SpliceAI 0.008 alone is insufficient.
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Reasoning
The variant is a missense substitution outside the VCEP-defined clinically important BRCA1 domains, so it is within the scope of the VCEP's repurposed BP7_Strong (RNA) path for missense/in-frame variants outside those domains. That path requires well-established in vitro or in vivo functional evidence showing no damaging effect as measured by an mRNA-only assay. The available evidence contains an in silico SpliceAI result (maximum delta 0.008) but no qualifying variant-specific mRNA assay result. SpliceAI alone does not satisfy the BP7_Strong (RNA) requirement, so BP7 cannot be assessed from the available evidence.
VCEP rule
Well-established in vitro or in vivo functional studies shows no damaging effect on protein function as measured by effect on mRNA transcript profile – mRNA assay only. ... Apply as BP7_Strong (RNA) for intronic, silent, and missense/in-frame variants located outside a (potentially) clinically important functional domain.
Evidence considered
The VCEP repurposes BP7 as BP7_Strong (RNA) for intronic, silent, and missense/in-frame variants located outside a potentially clinically important functional domain when a well-established mRNA-only assay shows no damaging effect.
The VCEP-defined BRCA1 domains are RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857; p.Ala1082Val is outside all three.
SpliceAI predicts a maximum delta score of 0.008, but this is an in silico prediction rather than the required well-established mRNA-only functional assay.
The searched VCEP full-text files and case evidence did not provide a qualifying variant-specific mRNA-only assay result for c.3245C>T, p.Ala1082Val, or p.A1082V.
Still missing
No qualifying variant-specific mRNA-only assay result was identified in the available case evidence.
No variant-specific entry was found after searching SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, and PMID_22505045_Houdayer_2012_HumMutat.pdf.txt for c.3245C>T, p.Ala1082Val, and p.A1082V.
Not applicable · 12· recorded as not applicableShow reasons ▾Hide reasons ▴PVS1N/ANot applicable: c.3245C>T causes p.Ala1082Val, a missense substitution outside the ENIGMA null-variant PVS1 scope.
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Reasoning
PVS1 is not applicable because NM_007294.4:c.3245C>T is a missense substitution, NP_009225.1:p.(Ala1082Val), not a null variant. The ENIGMA BRCA1 specification limits this criterion to null variants and directs PVS1 application through its decision tree for initiation, nonsense/frameshift, deletion, duplication, and canonical donor/acceptor splice-site variants. The governing Table 4, full specification, appendices, and Houdayer paper were searched for c.3245C>T, p.Ala1082Val, and p.A1082V; no variant-level entry was found.
VCEP rule
Null variant in a gene where loss of function is a known mechanism of disease. ... In alignment with SVI recommendations for PVS1 code application, evidence strength and description has been separated for different variant types. Apply according to PVS1 flowchart, which considers knowledge of clinically important functional domains. For predicted protein termination codon (PTC) variants, apply with exon-specific weights derived for the PM5 (PTC) code (see description below).
Evidence considered
Case normalization: NM_007294.4:c.3245C>T produces NP_009225.1:p.(Ala1082Val) / p.(A1082V) and is classified as missense.
ENIGMA Specifications v1.2, Table 1, PVS1 row: PVS1 is defined for a null variant in a gene where loss of function is a known mechanism of disease; the specification identifies the applicable PVS1 decision-tree variant types as initiation, nonsense/frameshift, deletion, duplication, and donor/acceptor ±1,2 splice-site variants.
ENIGMA Specifications Table 4, Specifications v1.2, Appendices v1.2, and PMID_22505045_Houdayer_2012_HumMutat.pdf.txt: searched for c.3245C>T, p.Ala1082Val, and p.A1082V; no matching variant-level entry was found.
Still missing
No entry for c.3245C>T, p.Ala1082Val, or p.A1082V was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
No entry for c.3245C>T, p.Ala1082Val, or p.A1082V was found in Specifications_V1.2_2024-11-18.docx.txt.
No entry for c.3245C>T, p.Ala1082Val, or p.A1082V was found in Appendices_V1.2_2024-11-18.docx.txt.
No entry for c.3245C>T, p.Ala1082Val, or p.A1082V was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
PS2VCEPNot applicable: the ENIGMA specification explicitly says PS2 should not be used because de novo predictive capacity is uncalibrated for relatively common BRCA1/2-related cancers.
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Reasoning
PS2 is not applicable under the ENIGMA BRCA1/2 VCEP because the specification explicitly says not to use this criterion; it cites the relatively common occurrence of BRCA1/2-related cancers and the absence of calibration for de novo observations.
VCEP rule
Do not use ... BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.
Evidence considered
ENIGMA BRCA1/2 Specification v1.2, PS2 entry: PS2 is marked ‘Do not use’; the stated reason is that BRCA1/2-related cancers occur relatively commonly and de novo predictive capacity is not calibrated.
PM1VCEPNot applicable: ENIGMA explicitly says PM1 is not used, and Ala1082 lies outside the listed BRCA1 critical functional domains.
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Reasoning
The ENIGMA specification explicitly marks PM1 as not to be used and states that it is considered as a component of the bioinformatic analysis under PP3/BP4. The variant residue Ala1082 is also outside the VCEP-defined BRCA1 RING domain (aa 2-101), coiled-coil domain (aa 1391-1424), and BRCT repeats (aa 1650-1857).
VCEP rule
Do not use
Considered as component of bioinformatic analysis (PP3/BP4).
Evidence considered
Specifications V1.2 Table 1, PM1 row: PM1 is marked 'Do not use' and is considered as a component of bioinformatic analysis (PP3/BP4).
Appendix J/Table 16 lists the BRCA1 domains used for domain-based analysis as RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857.
The case variant is p.Ala1082Val; residue 1082 is outside all three ENIGMA-defined BRCA1 domains.
PM4VCEPNot applicable: p.Ala1082Val is a missense substitution with no protein length change, while ENIGMA explicitly says PM4 is not used.
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Reasoning
PM4 is not applicable under the ENIGMA BRCA1 specification: it is restricted to protein length changes from in-frame deletions/insertions in a non-repeat region or stop-loss variants, and the specification explicitly states not to use it. This variant is a missense substitution, with no protein length change.
VCEP rule
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. ... Do not use ... Considered as component of bioinformatic analysis (PP3/BP4).
Evidence considered
Case normalization: NM_007294.4:c.3245C>T produces NP_009225.1:p.(Ala1082Val) / p.(A1082V), a missense substitution with no in-frame insertion/deletion or stop-loss consequence.
ENIGMA Specifications v1.2, Table 1, PM4 row: the criterion is described for protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants, followed by the explicit instruction 'Do not use'.
Still missing
No entry for c.3245C>T, p.Ala1082Val, or p.A1082V was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
No entry for c.3245C>T, p.Ala1082Val, or p.A1082V was found in Specifications_V1.2_2024-11-18.docx.txt.
No entry for c.3245C>T, p.Ala1082Val, or p.A1082V was found in Appendices_V1.2_2024-11-18.docx.txt.
No entry for c.3245C>T, p.Ala1082Val, or p.A1082V was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
PM5N/ANot applicable: classic missense PM5 is excluded by ENIGMA, and PM5_PTC is limited to PVS1-annotated protein-termination variants.
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Reasoning
For BRCA1, the ENIGMA specification marks classic missense PM5 as not to be used because some residues can harbor both pathogenic and non-pathogenic substitutions. The repurposed PM5_PTC code applies only to protein-termination-codon variants annotated with PVS1; this variant is a missense substitution, not a PTC variant.
VCEP rule
Do not use
Considered as component of bioinformatic analysis (PP3/BP4). ... Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before. Use to justify additional weight for PTC variants annotated as PVS1.
Evidence considered
Specifications V1.2 Table 1, PM5 row: classic PM5 is marked 'Do not use'; the reason given is that some residues can harbor pathogenic and non-pathogenic substitutions.
Specifications V1.2 Table 1 and Table 4 readme: PM5_PTC is for protein termination codon variants annotated as PVS1 and is applied only to genomic PTC changes, not splicing.
The case variant is NM_007294.4:c.3245C>T, p.Ala1082Val, a missense substitution rather than a protein-termination-codon variant.
PM6VCEPNot applicable: the ENIGMA specification explicitly says PM6 should not be used because de novo predictive capacity is uncalibrated for relatively common BRCA1/2-related cancers.
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Reasoning
PM6 is not applicable under the ENIGMA BRCA1/2 VCEP because the specification explicitly says not to use this criterion; it cites the relatively common occurrence of BRCA1/2-related cancers and the absence of calibration for de novo observations.
VCEP rule
Do not use ... BRCA1/2-related cancers occur relatively commonly. No information to calibrate the predictive capacity of de novo occurrences.
Evidence considered
ENIGMA BRCA1/2 Specification v1.2, PM6 entry: PM6 is marked ‘Do not use’; the stated reason is that BRCA1/2-related cancers occur relatively commonly and de novo predictive capacity is not calibrated.
PP2VCEPNot applicable: ENIGMA excludes PP2 because missense variants are not a common BRCA1 pathogenic mechanism and benign missense variation is frequent.
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Reasoning
The ENIGMA specification explicitly marks PP2 as not to be used and states that missense variants are not a common mechanism of pathogenicity for BRCA1 and BRCA2; it further cites a high frequency of benign missense variants.
VCEP rule
Do not use
High frequency of benign missense variants.
Evidence considered
Specifications V1.2 Table 1, PP2 row: PP2 is marked 'Do not use' because of a high frequency of benign missense variants.
Appendix J/Table 16 states that missense variants are not a common mechanism of pathogenicity for BRCA1 and BRCA2.
PP5VCEPNot applicable: ENIGMA explicitly says PP5 is not for use, so no reputable-source pathogenic report can activate this criterion.
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Reasoning
The ENIGMA VCEP explicitly states that PP5 is not for use. This criterion is therefore not applicable regardless of the ClinVar submissions or other reputable-source classifications for this variant.
VCEP rule
Reputable source recently reports variant as pathogenic but the evidence is not available to the laboratory to perform an independent evaluation. ... Do not use
Evidence considered
ENIGMA BRCA1/2 Specifications v1.2, PP5: the criterion is marked Do not use.
The exact variant notations c.3245C>T, p.Ala1082Val, and p.A1082V were searched in the governing VCEP full-text files; no variant-level PP5 entry was found.
BP2VCEPNot applicable: the ENIGMA specification states BP2 is not used and is applied only in the context of BS2.
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Reasoning
BP2 is not applicable under the ENIGMA BRCA1 Version 1.2 specification. Although the criterion description concerns observation in trans with a pathogenic variant or in cis with a pathogenic variant, the VCEP explicitly states that BP2 is not to be used and is applied only in the context of BS2.
VCEP rule
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder, or observed in cis with a pathogenic variant in any inheritance pattern
Do not use
Applied only in the context of BS2.
Evidence considered
ENIGMA Specifications V1.2, BP2 entry: the description covers trans or cis observation with a pathogenic variant, followed by the governing instructions "Do not use" and "Applied only in the context of BS2."
BP3VCEPNot applicable: p.Ala1082Val is not an in-frame deletion or insertion, and ENIGMA explicitly says BP3 is not used.
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Reasoning
BP3 is not applicable under the ENIGMA BRCA1 specification: it concerns in-frame deletions/insertions in a repetitive region without a known function, explicitly is not used, and is captured by bioinformatic tool prediction and domain analysis. This variant is a missense substitution, not an in-frame deletion or insertion.
VCEP rule
In-frame deletions/insertions in a repetitive region without a known function. ... Do not use ... Captured by bioinformatic tool prediction, and domain analysis. See Appendix J.
Evidence considered
Case normalization: NM_007294.4:c.3245C>T produces NP_009225.1:p.(Ala1082Val) / p.(A1082V), a missense substitution rather than an in-frame deletion or insertion.
ENIGMA Specifications v1.2, Table 1, BP3 row: the criterion is defined for in-frame deletions/insertions in a repetitive region without a known function, followed by the explicit instruction 'Do not use' and the note that it is captured by bioinformatic tool prediction and domain analysis.
Still missing
No entry for c.3245C>T, p.Ala1082Val, or p.A1082V was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
No entry for c.3245C>T, p.Ala1082Val, or p.A1082V was found in Specifications_V1.2_2024-11-18.docx.txt.
No entry for c.3245C>T, p.Ala1082Val, or p.A1082V was found in Appendices_V1.2_2024-11-18.docx.txt.
No entry for c.3245C>T, p.Ala1082Val, or p.A1082V was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
BP4N/ANot applicable: BP4's missense path requires a variant inside a VCEP-defined functional domain, whereas p.Ala1082Val lies outside all listed BRCA1 domains.
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Reasoning
The variant is a missense substitution outside the VCEP-defined BRCA1 clinically important functional domains. The VCEP BP4 missense path is limited to missense or in-frame variants inside such a domain with BayesDel no-AF ≤0.15 and SpliceAI ≤0.1. The other BP4 paths are for silent variants inside a domain or intronic variants outside the canonical donor/acceptor ±1,2 positions; neither applies to this missense variant. Therefore BP4 is not applicable before evidence sufficiency is considered. The observed scores (BayesDel no-AF -0.0316675 and SpliceAI maximum delta 0.008) do not expand the VCEP's stated scope.
VCEP rule
Apply BP4 for: ... Missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain, and no predicted impact via protein change or splicing (BayesDel predicted No Impact AND SpliceAI ≤0.1).
Evidence considered
The VCEP BP4 missense path requires a missense or in-frame variant inside a potentially clinically important functional domain with BayesDel no-AF ≤0.15 and SpliceAI ≤0.1.
The VCEP lists BRCA1 RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857 as the clinically important domains; p.Ala1082Val is outside these regions.
SpliceAI maximum delta is 0.008 and BayesDel no-AF is -0.0316675, but those values cannot make the out-of-domain missense variant eligible for the BP4 missense path.
BP6VCEPNot applicable: ENIGMA explicitly says BP6 is not for use, so reputable-source benign reports cannot activate this criterion.
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Reasoning
The ENIGMA VCEP explicitly states that BP6 is not for use. This criterion is therefore not applicable regardless of benign reports from reputable sources.
VCEP rule
Reputable source recently reports variant as benign but the evidence is not available to the laboratory to perform an independent evaluation ... Do not use
Evidence considered
ENIGMA BRCA1/2 Specifications v1.2, BP6: the criterion is marked Do not use.
The exact variant notations c.3245C>T, p.Ala1082Val, and p.A1082V were searched in the governing VCEP full-text files; no variant-level BP6 entry was found.
Every interpreted variant in BRCA1, mapped onto the exon structure of NM_007294.4. Select a row to find it on the plot.
BRCA1NM_007294.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in BRCA1—Select a row to find it on the plot; use the link to open its page.
Protein
Location
Classification
Link
gnomAD v4.1Allele count data not recorded
gnomAD v2.1Allele count data not recorded
gnomAD-Canada v1.0Allele 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 +132 bp
0.000
SpliceAI acceptor gainat -147 bp
0.008
SpliceAI donor lossat -187 bp
0.001
SpliceAI donor gainat +265 bp
0.000
Other predictors
REVEL
0.481
BayesDel
-0.032
How the predictions were used
PP3VCEPNot met: SpliceAI maximum delta 0.008 is below the VCEP PP3 splice threshold of ≥0.2, and the variant is outside the domain required for the protein-impact path.
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Reasoning
The variant is missense p.(Ala1082Val) and lies outside the VCEP-defined BRCA1 clinically important domains (RING aa 2-101, coiled-coil aa 1391-1424, BRCT repeats aa 1650-1857), so the PP3 protein-impact path does not apply. The VCEP separately permits PP3 for predicted splicing in missense variants irrespective of domain location, requiring SpliceAI ≥0.2. The case SpliceAI maximum delta score is 0.008, below that threshold, so the splice path is not met. BayesDel no-AF is -0.0316675, but it is not usable for the PP3 protein path because the variant is outside the required domain; it also does not meet the VCEP BRCA1 protein-impact threshold of ≥0.28. No governing VCEP table entry for c.3245C>T, p.Ala1082Val, or p.A1082V was found in the searched supplementary or full-text VCEP files.
VCEP rule
Apply PP3 for missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain and predicted impact via protein change (BayesDel predicted Impact). ... Apply PP3 for predicted splicing (SpliceAI ≥0.2) for silent, missense/in-frame (irrespective of location in clinically important functional domain) and for intronic variants outside of the donor and acceptor ±1,2 positions.
Evidence considered
The VCEP PP3 rule applies to missense or in-frame variants inside a potentially clinically important functional domain when BayesDel no-AF predicts protein impact, and separately applies to predicted splicing with SpliceAI ≥0.2 for missense variants irrespective of domain location.
For BRCA1, the VCEP defines protein-impact PP3 at BayesDel no-AF ≥0.28; the observed BayesDel no-AF score is -0.0316675, but the missense is outside the required clinically important domain.
SpliceAI results for NM_007294.4:c.3245C>T are DS_AG 0.008, DS_AL 0.0, DS_DG 0.0, and DS_DL 0.001; maximum delta score 0.008, below the VCEP PP3 threshold.
The VCEP-defined BRCA1 domains are RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857; p.Ala1082Val is outside all three.
SupplementaryTables_V1.2_2024-11-18.xlsx.txt was searched for c.3245C>T, p.Ala1082Val, and p.A1082V; no matching row was found.
Still missing
No variant-specific entry was found after searching SupplementaryTables_V1.2_2024-11-18.xlsx.txt for c.3245C>T, p.Ala1082Val, and p.A1082V.
No variant-specific entry was found after searching Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, and PMID_22505045_Houdayer_2012_HumMutat.pdf.txt for c.3245C>T, p.Ala1082Val, and p.A1082V.
BP7VCEPNot assessed: The variant is eligible for BP7_Strong (RNA), but no qualifying mRNA-only assay result is available; SpliceAI 0.008 alone is insufficient.
Details ▾Hide ▴
Reasoning
The variant is a missense substitution outside the VCEP-defined clinically important BRCA1 domains, so it is within the scope of the VCEP's repurposed BP7_Strong (RNA) path for missense/in-frame variants outside those domains. That path requires well-established in vitro or in vivo functional evidence showing no damaging effect as measured by an mRNA-only assay. The available evidence contains an in silico SpliceAI result (maximum delta 0.008) but no qualifying variant-specific mRNA assay result. SpliceAI alone does not satisfy the BP7_Strong (RNA) requirement, so BP7 cannot be assessed from the available evidence.
VCEP rule
Well-established in vitro or in vivo functional studies shows no damaging effect on protein function as measured by effect on mRNA transcript profile – mRNA assay only. ... Apply as BP7_Strong (RNA) for intronic, silent, and missense/in-frame variants located outside a (potentially) clinically important functional domain.
Evidence considered
The VCEP repurposes BP7 as BP7_Strong (RNA) for intronic, silent, and missense/in-frame variants located outside a potentially clinically important functional domain when a well-established mRNA-only assay shows no damaging effect.
The VCEP-defined BRCA1 domains are RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857; p.Ala1082Val is outside all three.
SpliceAI predicts a maximum delta score of 0.008, but this is an in silico prediction rather than the required well-established mRNA-only functional assay.
The searched VCEP full-text files and case evidence did not provide a qualifying variant-specific mRNA-only assay result for c.3245C>T, p.Ala1082Val, or p.A1082V.
Still missing
No qualifying variant-specific mRNA-only assay result was identified in the available case evidence.
No variant-specific entry was found after searching SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, and PMID_22505045_Houdayer_2012_HumMutat.pdf.txt for c.3245C>T, p.Ala1082Val, and p.A1082V.
BP4N/ANot applicable: BP4's missense path requires a variant inside a VCEP-defined functional domain, whereas p.Ala1082Val lies outside all listed BRCA1 domains.
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Reasoning
The variant is a missense substitution outside the VCEP-defined BRCA1 clinically important functional domains. The VCEP BP4 missense path is limited to missense or in-frame variants inside such a domain with BayesDel no-AF ≤0.15 and SpliceAI ≤0.1. The other BP4 paths are for silent variants inside a domain or intronic variants outside the canonical donor/acceptor ±1,2 positions; neither applies to this missense variant. Therefore BP4 is not applicable before evidence sufficiency is considered. The observed scores (BayesDel no-AF -0.0316675 and SpliceAI maximum delta 0.008) do not expand the VCEP's stated scope.
VCEP rule
Apply BP4 for: ... Missense or in-frame insertion, deletion or delins variants inside a (potentially) clinically important functional domain, and no predicted impact via protein change or splicing (BayesDel predicted No Impact AND SpliceAI ≤0.1).
Evidence considered
The VCEP BP4 missense path requires a missense or in-frame variant inside a potentially clinically important functional domain with BayesDel no-AF ≤0.15 and SpliceAI ≤0.1.
The VCEP lists BRCA1 RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857 as the clinically important domains; p.Ala1082Val is outside these regions.
SpliceAI maximum delta is 0.008 and BayesDel no-AF is -0.0316675, but those values cannot make the out-of-domain missense variant eligible for the BP4 missense path.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.481. BayesDel score = -0.0316675.
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
Ovarian cancer cell line panel (OCCP): clinical importance of in vitro morphological subtypes.
Beaufort CM et al. · 2014
The paper does not mention BRCA1 c.3245C>T or NP_009225.1:p.(A1082V). It reports BRCA1-related findings from a characterization study of ovarian cancer cell lines, including a BRCA1-null line carrying a different germline mutation; no result for this variant is provided.
Germline mutations in BRCA1 and BRCA2 have been associated with response to platinum drugs. However, there was no clear association between response to platinum and mutation status or expression of BRCA1 and BRCA2 in our experiments (data not shown).
Materials and Methods, Cell lines and culturing; Results, Response to chemotherapeutics
Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots".
Dines JN et al. · 2020
The paper does not explicitly mention BRCA1 c.3245C>T or NP_009225.1:p.(A1082V). It characterizes BRCA1 exon 11 as a missense coldspot using curated ClinVar data and Bayesian regional analysis, without reporting a variant-specific functional assay result for this variant.
Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement.
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 Uncertain significance (3 clinical laboratories). (ClinVarID = 441288)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.481. BayesDel score = -0.0316675.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA1, 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.
This variant was interpreted by pipeline 11.0.02.
The current version is 11.0.07.
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