The BRCA1 NM_007294.4:c.3541G>A (NP_009225.1:p.(Val1181Ile)) missense variant has previously been reported in somatic cancers (COSMIC; COSV105897766, n = 3 times). Based on available guidelines, this variant is considered to be Benign. This variant is considered to be Benign by the VCEP (Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA); ClinVar ID 54911).
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
This variantScenario
BenignPathogenic
Benign.A benign classification under the recorded framework.
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.
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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.
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 3
BP1Strong
BP1 · strong
Met at strong: residue 1181 is outside all defined BRCA1 critical domains and SpliceAI max delta 0.003 is below the ≤0.1 threshold.
BP5Very strong
BP5 · very strong
Met, Very Strong: Li et al. clinical-history LR 0.0005098224064769393 ≤ 0.00285, satisfying the ENIGMA BP5 Very Strong threshold.
BP6Supporting
BP6 · supporting
Not applicable: the ENIGMA specification explicitly states Do not use BP6, so the ClinVar benign assertion cannot establish BP6.
Recorded classification: Benign
Benign: BP5 (very strong benign) plus BP6 (supporting benign) satisfy the ENIGMA VCEP benign 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
73 / 1,614,060 alleles
gnomAD v4.1: 73 / 1,614,060 alleles. Recorded AF 4.52276e-05. Recorded homozygote count 1.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.56418e-05; MAF= 0.00756%, 19/251184 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.000457397; MAF= 0.04574%, 14/30608 alleles, homozygotes = 1); grpmax FAF= 0.00027594.
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: 3 met · 4 not met · 10 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
For the requested codon, residue, and domain criteria, BP1_Strong is met; PM1, PM5, and PP2 are not applicable under explicit ENIGMA rules; PS1 remains not assessed because a qualifying pathogenic or likely pathogenic same-amino-acid comparator was not established.
The queried variant is BRCA1 NM_007294.4:c.3541G>A, p.Val1181Ile (p.V1181I), a missense variant at residue 1181 outside the VCEP-defined critical functional domains.
The ClinGen ENIGMA BRCA1/2 VCEP Specification v1.2 governs PS3 and BS3 and directs variant-specific functional adjudication to calibrated functional assay data in Specifications Table 9 and supporting supplementary datasets.
The exact variant notations c.3541G>A, p.Val1181Ile, and p.V1181I were searched across all named governing VCEP files; Table 9 had no entry, and the supplementary exact-match rows did not contain functional assay results or code assignments.
PS3 and BS3 are both not_assessed because no qualifying damaging or no-damaging protein/combined mRNA functional result is available; the exact variant's multifactorial SuppT1 record is not functional evidence.
Among the requested criteria, BP5_VeryStrong is met because the exact BRCA1 c.3541G>A clinical-history LR is 0.0005098224064769393 and 0.0005098224064769393 ≤ 0.00285.
PP4 is not met because 0.0005098224064769393 ≥ 2.08 is false; PS4 is not assessed because no qualifying matched case-control statistics are available.
PP5 and BP6 are not applicable because the ENIGMA specification explicitly says Do not use for both criteria.
For NM_007294.4:c.3541G>A (NP_009225.1:p.(Val1181Ile)), the VCEP computational criteria resolve as PP3 not met because SpliceAI maximum delta is 0.003 versus the >=0.2 threshold, BP4 not applicable because the missense residue is outside the required functional-domain scope, and BP7 not assessed because no qualifying mRNA-only assay supports BP7_Strong (RNA).
Population evidence is benign-directional but does not support BA1 because the maximum specified FAF is below 0.001.
BS1 has a frequency pattern consistent with the Strong threshold in gnomAD v2.1 non-cancer exomes, but cannot be assigned without the governing read-depth requirement.
PM2 is not met because the variant is present in both governing non-cancer gnomAD datasets.
BS2 is not assessed because the only homozygote observation is frequency-based gnomAD evidence, which the ENIGMA specification excludes from BS2 point assignment.
No criteria match.
Met · 3
BP1StrongVCEPMet at strong: residue 1181 is outside all defined BRCA1 critical domains and SpliceAI max delta 0.003 is below the ≤0.1 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. p.Val1181Ile is a missense substitution at residue 1181, outside the VCEP-defined BRCA1 RING 2-101, coiled-coil 1391-1424, and BRCT 1650-1857 domains. SpliceAI maximum delta is 0.003, meeting the VCEP threshold of ≤0.1. BP1_Strong is therefore met.
VCEP rule
Apply BP1_Strong for silent substitution, missense or in-frame insertion, deletion or delins variants outside a (potentially) clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1).
Evidence considered
ENIGMA BP1_Strong rule: applies to missense variants outside a potentially clinically important functional domain with no predicted splicing (SpliceAI ≤0.1).
Variant consequence: NM_007294.4:c.3541G>A is a missense substitution producing p.Val1181Ile.
ENIGMA BRCA1 domain boundaries: RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857; residue 1181 is outside all three.
SpliceAI case result: max delta score = 0.003, satisfying the ≤0.1 requirement.
BP5Very strongVCEPMet, Very Strong: Li et al. clinical-history LR 0.0005098224064769393 ≤ 0.00285, satisfying the ENIGMA BP5 Very Strong threshold.
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Reasoning
ENIGMA BP5 is used only for multifactorial clinical likelihood evidence against pathogenicity. Li et al. 2020 Supplementary Table 3 reports LR = 0.0005098224064769393 for the exact BRCA1 c.3541G>A row. The governing BP5 Very Strong operator is ≤0.00285:1, and the required comparison is 0.0005098224064769393 ≤ 0.00285? Yes. Therefore BP5_VeryStrong is met.
VCEP rule
Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data. ... BP5_VeryStrong – LR ≤0.00285:1
Evidence considered
Li et al. 2020 Supplementary Table 3, exact row Gene=BRCA1 and HGVS_Nucleotide=c.3541G>A: LOG(LR)=-3.292581081390381; LR=0.0005098224064769393; N_Probands=9.
The governing BP5 Very Strong operator is ≤; explicit comparison: 0.0005098224064769393 ≤ 0.00285? Yes.
BP6SupportingVCEPNot applicable: the ENIGMA specification explicitly states Do not use BP6, so the ClinVar benign assertion cannot establish BP6.
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Reasoning
Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Benign.
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
ClinVar variation 54911 identifies NM_007294.4(BRCA1):c.3541G>A (p.Val1181Ile) as benign with reviewed-by-expert-panel status.
The VCEP specification's BP6 entry states Do not use, so the ClinVar assertion is not applied to BP6.
PM2VCEPNot met: the variant is present in both required controls, at 19/236686 alleles in v2.1 non-cancer exomes and 2/147900 in v3.1 non-cancer genomes.
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Reasoning
The ENIGMA PM2 Supporting rule requires absence from controls in both gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, with regional average read depth at least 25. The variant is present in both required datasets: 19/236686 alleles with one homozygote in v2.1 non-cancer exomes and 2/147900 alleles with no homozygotes in v3.1 non-cancer genomes. Because it is not absent from either specified control dataset, PM2 is not met.
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
ENIGMA PM2 Supporting rule: absent from controls in an outbred population from gnomAD v2.1 non-cancer exome-only and gnomAD v3.1 non-cancer genome datasets; regional average read depth must be ≥25.
GNOMAD_V2_1_NON_CANCER: c.3541G>A is present at AF 8.02751e-05, 19/236686 alleles, homozygotes=1.
GNOMAD_V3_1_NON_CANCER: c.3541G>A is present at AF 1.35227e-05, 2/147900 alleles, homozygotes=0.
ENIGMA Supplementary Table 7, row BRCA1 c.3541G>A / p.(Val1181Ile): gnomAD-derived outbred frequency data include 19 alleles and one homozygote; the variant is not absent from controls.
PP3VCEPNot met: SpliceAI maximum delta score 0.003 is below the VCEP PP3 splice-impact threshold of 0.2.
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Reasoning
The variant is a missense substitution, so the VCEP's PP3 splice-prediction path applies irrespective of functional-domain location. The governing threshold is SpliceAI >=0.2; the available SpliceAI result has a maximum delta score of 0.003, below that threshold. The PP3 protein-impact path is not applicable because p.Val1181Ile is at residue 1181, outside the VCEP-defined BRCA1 clinically important domains (RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857).
VCEP rule
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
ClinGen ENIGMA BRCA1 specification v1.2: PP3 applies to predicted splicing with SpliceAI >=0.2 for silent and missense/in-frame variants irrespective of location in a clinically important functional domain.
Case SpliceAI result for NM_007294.4:c.3541G>A (NP_009225.1:p.(Val1181Ile)): DS_AG 0.000, DS_AL 0.003, DS_DG 0.001, DS_DL 0.001; maximum delta score 0.003.
ClinGen ENIGMA BRCA1 specification v1.2 defines clinically important BRCA1 domains as RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857; residue 1181 is outside these domains, so the PP3 protein-impact BayesDel path does not apply.
PP4VCEPNot met: Li et al. clinical-history LR 0.0005098224064769393 ≥ 2.08? No, so the ENIGMA PP4 supporting threshold is not reached.
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Reasoning
ENIGMA PP4 is restricted to combined multifactorial clinical likelihood evidence toward pathogenicity. The exact BRCA1 c.3541G>A row in Li et al. 2020 Supplementary Table 3 reports LOG(LR) = -3.292581081390381 and LR = 0.0005098224064769393. The governing PP4 supporting threshold is LR ≥2.08:1, so the required comparison is 0.0005098224064769393 ≥ 2.08? No. The value is in the opposite direction and does not meet PP4 at any pathogenic strength.
VCEP rule
Breast cancer is very common and has a high degree of genetic heterogeneity (caused by pathogenic variants in numerous genes). Use ONLY to capture combined LR towards pathogenicity, based on multifactorial likelihood clinical data. ... PP4 - LR ≥2.08:1
Evidence considered
Li et al. 2020 Supplementary Table 3, exact row Gene=BRCA1 and HGVS_Nucleotide=c.3541G>A: LOG(LR)=-3.292581081390381; LR=0.0005098224064769393; N_Probands=9.
The governing PP4 operator is ≥; explicit comparison: 0.0005098224064769393 ≥ 2.08? No. The same value is also below the Moderate (4.3), Strong (18.7), and Very Strong (350) thresholds.
BA1VCEPNot met: maximum specified non-cancer FAF is 0.00027671, below the ENIGMA BA1 threshold of >0.001.
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Reasoning
The ENIGMA BA1 threshold is FAF >0.001 in the specified non-cancer, non-founder gnomAD populations. The highest available specified FAF is 0.00027671 in gnomAD v2.1 non-cancer exomes, and gnomAD v3.1 non-cancer genomes has FAF 0.00000488; both are below 0.001. The variant therefore does not meet BA1, irrespective of the unavailable depth metric.
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.
GNOMAD_V2_1_NON_CANCER: c.3541G>A present in non-cancer exomes at AF 8.02751e-05, 19/236686 alleles, homozygotes=1; maximum population FAF=0.00027671 in South Asians.
GNOMAD_V3_1_NON_CANCER: c.3541G>A present in non-cancer genomes at AF 1.35227e-05, 2/147900 alleles, homozygotes=0; maximum population FAF=0.00000488 in the European non-Finnish population.
ENIGMA Supplementary Table 7, row BRCA1 c.3541G>A / p.(Val1181Ile): maximum MAF 0.0004587456583, frequency category >0.0001 MAF <=0.001.
PS1VCEPNot assessed: SpliceAI max delta is 0.003, but no qualifying pathogenic or likely pathogenic comparator producing the same p.Val1181Ile substitution was established.
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Reasoning
The ENIGMA rule requires a previously classified pathogenic or likely pathogenic variant producing the same missense substitution, with no confirmed or predicted splice effect. The case evidence identifies p.Val1181Ile/c.3541G>A as benign or uncertain in the consulted literature, including V1181I in Table 3 of Judkins et al. and p.Val1181Ile in Table 3 of Konecny et al., but does not establish a qualifying pathogenic or likely pathogenic same-amino-acid comparator. SpliceAI max delta is 0.003, satisfying the no-splicing condition, but the required pathogenic comparator evidence is unresolved.
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
ENIGMA Specifications v1.2 PS1 rule: PS1 requires a predicted missense substitution matching a previously classified pathogenic variant acting through protein change, with SpliceAI ≤0.1; PS1_Moderate applies for a previously established likely pathogenic variant.
SpliceAI case result: maximum delta score 0.003, below the VCEP ≤0.1 no-splicing condition.
Judkins et al. 2005, Table 3: V1181I is listed as a variant of uncertain clinical significance (U), associated with BRCA1 haplotypes 1 and 2; no pathogenic classification is given.
Konecny et al. 2011, Tables 3-4: p.Val1181Ile is reported as c.3524G>A, not the queried c.3541G>A, and classified as a missense variant of uncertain clinical significance; the reported predictions were PolyPhen benign 0.35, Align-GVGD C25, and PMut neutral 0.08.
Still missing
No previously classified pathogenic or likely pathogenic BRCA1 variant producing p.Val1181Ile was identified in the governing VCEP materials or consulted paper extracts.
PS3VCEPNot assessed: no PS3/BS3-calibrated functional assay entry was found for c.3541G>A in ENIGMA Table 9 or the supplementary functional datasets.
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Reasoning
The ClinGen ENIGMA BRCA1/2 VCEP specification v1.2 requires well-established functional studies supportive of a damaging effect, with PS3 applied to assays measuring protein only or mRNA and protein combined, and directs variant-specific calibrated code assignment to Specifications Table 9. NM_007294.4:c.3541G>A (p.Val1181Ile; p.V1181I) has no matching entry in Specifications_Table9_V1.2_2024-11-18.xlsx. The same three variant notations were searched in SupplementaryTables_V1.2_2024-11-18.xlsx; the exact c.3541G>A row appears in the reference/frequency data but does not provide a functional assay result or PS3/BS3 assignment, and no matching functional-assay entry was found. Specifications_V1.2_2024-11-18.docx and Appendices_V1.2_2024-11-18.docx provide the governing rules and calibration context but no variant-specific functional result for this substitution. HUMU-40-1557-s001.xlsx contains the exact variant in SuppT1, with a benign multifactorial classification and no functional assay result populated. Therefore, no VCEP-governed damaging functional result is available to meet PS3, so PS3 is not_assessed rather than not_met.
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 BRCA1/2 VCEP v1.2 PS3 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; use Specifications Table 9 for calibrated published-assay code recommendations.
Specifications_Table9_V1.2_2024-11-18.xlsx: direct searches for c.3541G>A, p.Val1181Ile, and p.V1181I returned no matching variant entry.
SupplementaryTables_V1.2_2024-11-18.xlsx: direct searches for c.3541G>A, p.Val1181Ile, and p.V1181I found the exact c.3541G>A/p.(Val1181Ile) reference row, but no variant-specific functional assay result or PS3/BS3 code assignment; the relevant row cites Parsons et al. 2019 (PMID 31131967) for multifactorial data.
HUMU-40-1557-s001.xlsx, SuppT1 row BRCA1 c.3541G>A/p.(Val1181Ile)/V1181I: combined multifactorial data are reported, but the functional-assay fields are unpopulated for this variant.
Specifications_V1.2_2024-11-18.docx and Appendices_V1.2_2024-11-18.docx: governing PS3 functional-assay rules and calibration guidance were present, but no variant-specific assay result was found for the searched notations.
Still missing
No entry for c.3541G>A, p.Val1181Ile, or p.V1181I was found in Specifications_Table9_V1.2_2024-11-18.xlsx, the governing calibrated PS3/BS3 table.
No variant-specific functional-assay entry for c.3541G>A, p.Val1181Ile, or p.V1181I was found in SupplementaryTables_V1.2_2024-11-18.xlsx ST4/ST5/ST6; the exact variant occurs elsewhere in that file without a functional result.
Specifications_V1.2_2024-11-18.docx and Appendices_V1.2_2024-11-18.docx were searched for the three variant notations; they contain the governing functional rules but no variant-specific assay result.
HUMU-40-1557-s001.xlsx has an exact SuppT1 row for c.3541G>A, but it contains multifactorial/frequency data and no functional assay result for this variant.
PS4VCEPNot assessed: variant-specific reports lack matched control counts or a case-control p-value, odds ratio, and confidence interval meeting the ENIGMA PS4 rule.
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Reasoning
The ENIGMA rule requires a case-control study with p-value ≤0.05, OR ≥4, and a lower confidence interval excluding 2.0, with ethnicity- and country-matched controls. The reviewed variant-specific reports do not provide a qualifying affected-versus-control comparison: PMID:21203900 reports p.Val1181Ile in 1 of 117 Slovak families with BRCA1 uncertain variants but gives no control count or case-control statistic, and PMID:16267036 lists V1181I in a clinical-testing dataset without variant-specific controls or an OR. The literature_pass.json packet has an empty ai_classified_papers list, so no additional already-classified PS4 paper was available to verify. PS4 cannot be evaluated from the available evidence.
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). ... Case dataset should be ethnicity and country-matched to control dataset.
Evidence considered
PMID:21203900, Results Tables 3-4: p.Val1181Ile/c.3524G>A was reported in 1 of 117 families with BRCA1 uncertain variants; the paper provides no unaffected-control count, case-control p-value, OR, or confidence interval for the variant.
PMID:16267036, Table 3: V1181I was listed as a variant of uncertain clinical significance associated with BRCA1 haplotypes 1 and 2; the source reports no variant-specific control comparison or case-control statistic.
The searched VCEP full-text files included the exact notations c.3541G>A, p.Val1181Ile, and p.V1181I; no qualifying PS4 pre-assigned case-control code was found for this variant.
Still missing
No variant-specific ethnicity- and country-matched case-control dataset with p-value, OR, and lower confidence interval was identified.
literature_pass.json has no ai_classified_papers entries to verify for PS4.
PM3VCEPNot assessed: no Fanconi Anemia phenotype, qualifying second BRCA1 variant, phase, or Table 6 PM3 points are documented for c.3541G>A.
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Reasoning
The ENIGMA BRCA1 specification limits PM3 to patients with a phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia and co-occurrent variants in the same gene, with Table 6 points assigned for a P or LP variant in trans or homozygote, or for phase unknown. The available evidence does not document a Fanconi Anemia phenotype, chromosome-breakage testing, a co-occurrent pathogenic or likely pathogenic BRCA1 variant, phase, or a Table 6 qualifying proband observation. PMID:16267036 lists V1181I but does not report a variant-specific trans or phase observation. PMID:21203900 reports p.Val1181Ile under the discrepant coding notation c.3524G>A and does not report variant-specific phase, co-occurrence with a pathogenic variant, or an affected-proband Fanconi Anemia observation. PM3 therefore cannot be assigned from the available evidence.
VCEP rule
Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA), and co-occurrent variants in the same gene.
Evidence considered
Specifications_V1.2_2024-11-18.docx.txt, PM3 section and Table 6: PM3 applies to a patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia and co-occurrent variants in the same gene; a P or LP variant in trans or homozygote contributes 2 points, phase unknown contributes 1 point, and final assignment is PM3_Strong = 4 or more points, PM3 = 2 points, or PM3_Supporting = 1 point.
PMID:16267036, Table 3, V1181I (U) 1 2: V1181I is listed as uncertain clinical significance, but the source provides no variant-specific trans observation, phase result, segregation result, or Fanconi Anemia phenotype.
PMID:21203900, Tables 3 and 4: p.Val1181Ile is reported under c.3524G>A in one of 117 families carrying BRCA1 uncertain variants, with no associated pathogenic mutation and no variant-specific phase or segregation result.
Still missing
The governing file Specifications_V1.2_2024-11-18.docx.txt was searched for c.3541G>A, p.Val1181Ile, and p.V1181I; no variant-specific PM3 entry was found.
No case evidence documents Fanconi Anemia phenotype or DEB, MMC, or spontaneous chromosome-breakage results.
No case evidence documents a co-occurrent pathogenic or likely pathogenic BRCA1 variant, its VCEP classification, or phase in trans or cis.
PMID:16267036 reports V1181I but no specific trans or phase observation for this variant; PMID:21203900 reports p.Val1181Ile under c.3524G>A and no variant-specific phase or co-occurrence with a pathogenic variant.
PP1VCEPNot assessed: the exact variant row contains no segregation LR, so the VCEP's quantitative PP1 requirement cannot be evaluated or strength-assigned.
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Reasoning
PP1 requires co-segregation with disease in multiple affected family members measured by a quantitative co-segregation method and weighted by Bayes-score LR. The exact HUMU-40-1557 SuppT1 row for BRCA1 c.3541G>A lists no segregation LR, and the reviewed variant-specific paper findings provide no segregation analysis; therefore no PP1 strength can be assigned. The VCEP Specifications file was searched for c.3541G>A, p.Val1181Ile, and p.V1181I, with no variant-specific PP1 entry found.
VCEP rule
Co-segregation with disease in multiple affected family members
See Appendix I
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
Parsons et al. 2019, HUMU-40-1557 SuppT1 exact row BRCA1 c.3541G>A / p.(Val1181Ile) / V1181I: the Segregation LR field is blank; the row reports pathology LR 0.0168, co-occurrence LR 1.1767794364, family-history LR 0.16356565934, combined LR 0.0032336758341866886, and IARC class Benign, but these are not a quantitative co-segregation LR for PP1.
PMID:21203900 paper extract: the reported p.Val1181Ile entry uses the discrepant coding notation c.3524G>A and states that no variant-specific segregation analysis was provided.
PMID:16267036 paper extract: V1181I is listed as a variant of uncertain clinical significance, with no variant-specific segregation result reported.
Still missing
No quantitative co-segregation LR or family-level segregation dataset is available for this variant.
Specifications_V1.2_2024-11-18.docx was searched for c.3541G>A, p.Val1181Ile, and p.V1181I; no variant-specific PP1 entry was found.
HUMU-40-1557-s001.xlsx was searched and the exact variant row was found, but its Segregation LR field is blank.
BS1VCEPNot assessed: v2.1 non-cancer maximum FAF 0.00027671 exceeds the BS1 Strong threshold, but required read depth ≥20 is unavailable.
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Reasoning
The specified non-cancer gnomAD data meet the frequency portion of ENIGMA BS1: gnomAD v2.1 non-cancer exomes have maximum FAF 0.00027671, which is >0.0001 and would correspond to BS1 Strong, while gnomAD v3.1 non-cancer genomes have maximum FAF 0.00000488. However, the governing rule requires read depth of at least 20 for benign codes, and no read-depth value is available in the case evidence. The BS1 code cannot therefore be assigned conclusively.
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
ENIGMA BS1 rule: FAF >0.0001 is BS1 Strong; FAF >0.00002 and <=0.0001 is BS1 Supporting, using specified gnomAD non-cancer non-founder populations.
ENIGMA benign-code quality rule: benign codes must not be applied if read depth is <20; the case evidence does not provide read depth.
GNOMAD_V2_1_NON_CANCER: c.3541G>A present in non-cancer exomes at AF 8.02751e-05, 19/236686 alleles, homozygotes=1; maximum population FAF=0.00027671 in South Asians.
GNOMAD_V3_1_NON_CANCER: c.3541G>A present in non-cancer genomes at AF 1.35227e-05, 2/147900 alleles, homozygotes=0; maximum population FAF=0.00000488 in the European non-Finnish population.
ENIGMA Supplementary Table 7, row BRCA1 c.3541G>A / p.(Val1181Ile): frequency category >0.0001 MAF <=0.001 and maximum MAF 0.0004587456583; this is not a separate pre-assigned BS1 code.
Still missing
Read depth at the variant region for the governing gnomAD non-cancer datasets is not available; ENIGMA requires read depth ≥20 for BS1.
SupplementaryTables_V1.2_2024-11-18.xlsx was searched for c.3541G>A, p.Val1181Ile, and p.V1181I; no separate BS1 pre-assigned code was found beyond the frequency-category row.
BS2VCEPNot assessed: one gnomAD homozygote is frequency-based evidence, which ENIGMA excludes from BS2 point assignment without phenotyped cohort data.
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Reasoning
ENIGMA BS2 requires phenotyped clinical or research-cohort observations of the variant in healthy adults, with point assignment based on age, cancer status, phase, and co-occurring pathogenic or likely pathogenic variants, and absence of Fanconi Anemia features. The available evidence contains only one homozygote in gnomAD; ENIGMA expressly excludes frequency-based gnomAD observations from BS2 point assignment, so no BS2 points can be established.
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. ... ** Apply only for phenotyped individuals from clinical or research cohorts. NOT to be applied for data used to assign frequency-based codes; we have observed that variants observed as ≥2 homozygotes in GnomAD data (assumed unaffected adults of unspecified age) are already captured by the BA1 or BS1 frequency codes.
Evidence considered
ENIGMA BS2 rule: applied in the absence of features of recessive disease, namely Fanconi Anemia phenotype; final BS2 assignment is based on the sum of BS2-related points, with BS2 requiring at least 4 points.
ENIGMA Specifications Table 8: BS2 points require phenotyped individuals from clinical or research cohorts and are assigned using age/cancer-status, phase, and co-occurrence categories.
ENIGMA Appendix H/Table 8 stipulates that homozygotes observed in gnomAD are not to be used for BS2 because frequency-based observations are already captured by BA1 or BS1.
GNOMAD_V2_1_NON_CANCER: one homozygote is reported among 19/236686 alleles.
GNOMAD_V3_1_NON_CANCER: zero homozygotes are reported among 2/147900 alleles.
Still missing
No qualifying phenotyped clinical or research-cohort observation with age, cancer status, phase, co-occurring P/LP variant, and Fanconi Anemia assessment is available for BS2 point assignment.
BS3VCEPNot assessed: no BS3-calibrated protein or combined mRNA/protein assay result was found for c.3541G>A in the governing ENIGMA files.
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Reasoning
The ClinGen ENIGMA BRCA1/2 VCEP specification v1.2 requires well-established functional studies showing no damaging effect on protein function, using protein-only or mRNA-and-protein assays, and directs calibrated variant-specific recommendations to Specifications Table 9. NM_007294.4:c.3541G>A (p.Val1181Ile; p.V1181I) has no matching entry in Specifications_Table9_V1.2_2024-11-18.xlsx. SupplementaryTables_V1.2_2024-11-18.xlsx contains the exact variant in reference/frequency data, but no functional assay result or PS3/BS3 assignment for it. Specifications_V1.2_2024-11-18.docx and Appendices_V1.2_2024-11-18.docx contain the rules but no variant-specific functional result. HUMU-40-1557-s001.xlsx contains the exact SuppT1 row, but it reports multifactorial/frequency information and no functional assay result. Thus, the available VCEP-governed evidence does not establish a no-damaging functional effect, so BS3 is not_assessed rather than not_met.
VCEP rule
Well-established in vitro or in vivo functional studies shows no damaging effect on protein function. Assay measures effect via protein only OR mRNA and protein combined. See Specifications Table 9 for code recommendations from calibrated published assays. Also see Figure1C and Appendix E for details.
Evidence considered
ENIGMA BRCA1/2 VCEP v1.2 BS3 rule: well-established in vitro or in vivo functional studies show no damaging effect on protein function; assay measures effect via protein only OR mRNA and protein combined; use Specifications Table 9 for calibrated published-assay code recommendations.
Specifications_Table9_V1.2_2024-11-18.xlsx: direct searches for c.3541G>A, p.Val1181Ile, and p.V1181I returned no matching variant entry.
SupplementaryTables_V1.2_2024-11-18.xlsx: direct searches for c.3541G>A, p.Val1181Ile, and p.V1181I found the exact c.3541G>A/p.(Val1181Ile) reference row, but no variant-specific functional assay result or PS3/BS3 code assignment.
HUMU-40-1557-s001.xlsx, SuppT1 row BRCA1 c.3541G>A/p.(Val1181Ile)/V1181I: multifactorial data are reported, but the functional-assay fields are unpopulated for this variant.
Specifications_V1.2_2024-11-18.docx and Appendices_V1.2_2024-11-18.docx: governing BS3 functional-assay rules and calibration guidance were present, but no variant-specific assay result was found for the searched notations.
Still missing
No entry for c.3541G>A, p.Val1181Ile, or p.V1181I was found in Specifications_Table9_V1.2_2024-11-18.xlsx, the governing calibrated PS3/BS3 table.
No variant-specific functional-assay entry for c.3541G>A, p.Val1181Ile, or p.V1181I was found in SupplementaryTables_V1.2_2024-11-18.xlsx ST4/ST5/ST6; the exact variant occurs elsewhere in that file without a functional result.
Specifications_V1.2_2024-11-18.docx and Appendices_V1.2_2024-11-18.docx were searched for the three variant notations; they contain the governing functional rules but no variant-specific assay result.
HUMU-40-1557-s001.xlsx has an exact SuppT1 row for c.3541G>A, but it contains multifactorial/frequency data and no functional assay result for this variant.
BS4VCEPNot assessed: the exact variant row contains no segregation LR, so the VCEP's quantitative BS4 requirement cannot be evaluated or strength-assigned.
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Reasoning
BS4 requires lack of segregation in affected family members measured by a quantitative co-segregation method and weighted by Bayes-score LR. The exact HUMU-40-1557 SuppT1 row for BRCA1 c.3541G>A has no segregation LR, and reviewed variant-specific paper findings report no segregation analysis; absence of a reported result cannot establish BS4.
VCEP rule
Lack of segregation in affected members of a family.
See Appendix I.
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
Parsons et al. 2019, HUMU-40-1557 SuppT1 exact row BRCA1 c.3541G>A / p.(Val1181Ile) / V1181I: the Segregation LR field is blank, so no quantitative lack-of-segregation LR is available for BS4.
PMID:21203900 paper extract: the reported p.Val1181Ile entry uses the discrepant coding notation c.3524G>A and states that no variant-specific segregation analysis was provided.
PMID:16267036 paper extract: V1181I is listed as a variant of uncertain clinical significance, with no variant-specific segregation result reported.
Still missing
No quantitative non-segregation LR or family-level affected-member genotype data is available for this variant.
Specifications_V1.2_2024-11-18.docx was searched for c.3541G>A, p.Val1181Ile, and p.V1181I; no variant-specific BS4 entry was found.
HUMU-40-1557-s001.xlsx was searched and the exact variant row was found, but its Segregation LR field is blank.
BP7VCEPNot assessed: BP7_Strong (RNA) could cover this out-of-domain missense variant, but no qualifying mRNA-only assay result is available.
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Reasoning
The ordinary BP7 path is for silent or deeper intronic variants and therefore does not apply to this missense variant. However, the VCEP expressly repurposes BP7 as BP7_Strong (RNA) for missense variants outside a clinically important functional domain when well-established mRNA-only functional studies show no damaging effect. The variant is outside the defined domains, but no qualifying mRNA-only assay result is available in the reviewed case evidence, so this RNA-specific path cannot be assessed.
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
ClinGen ENIGMA BRCA1 specification v1.2: BP7 is ordinarily applied to silent variants inside a potentially clinically important functional domain if BP4 is met, or to intronic variants outside conserved donor or acceptor motif positions if BP4 is met.
ClinGen ENIGMA BRCA1 specification v1.2 separately states that BP7_Strong (RNA) applies to intronic, silent, and missense/in-frame variants located outside a potentially clinically important functional domain when well-established in vitro or in vivo functional studies show no damaging effect as measured by an mRNA-only assay.
p.Val1181Ile is outside the VCEP-defined BRCA1 clinically important domains, but the reviewed case evidence contains no qualifying mRNA-only functional assay result for this variant.
Still missing
No well-established mRNA-only functional assay result demonstrating no damaging effect was available for NM_007294.4:c.3541G>A; without it, the VCEP BP7_Strong (RNA) path cannot be evaluated.
Not applicable · 11· recorded as not applicableShow reasons ▾Hide reasons ▴PVS1N/ANot applicable: c.3541G>A is a missense substitution, whereas the VCEP PVS1 rule applies to null variants.
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Reasoning
NM_007294.4:c.3541G>A is annotated as the missense variant NP_009225.1:p.(Val1181Ile) (p.V1181I), not a nonsense, frameshift, canonical splice-site, initiation-codon, or exon-deletion variant. The ENIGMA BRCA1 VCEP PVS1 rule is restricted to null variants; therefore PVS1 is not applicable. The variant is in exon 10, but exon location does not convert a missense substitution into a PVS1-eligible null consequence.
VCEP rule
Null variant in a gene where loss of function is a known mechanism of disease.
ENIGMA Specifications v1.2, Table 1, PVS1: the criterion is defined for a null variant in a gene where loss of function is a known mechanism of disease; the specification directs application according to the PVS1 flowchart for null variant types.
PS2VCEPNot applicable: ENIGMA says PS2 must not be used because BRCA1/2-related cancers are relatively common and de novo predictive capacity is uncalibrated.
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Reasoning
The ENIGMA BRCA1 specification explicitly states that PS2 is not to be used: de novo occurrences are not calibrated because BRCA1/2-related cancers occur relatively commonly. This governing applicability rule prevents PS2 assessment regardless of whether a de novo observation were reported.
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 specification v1.2, Table 1, PS2: the criterion is marked Do not use because BRCA1/2-related cancers occur relatively commonly and no information calibrates de novo predictive capacity.
PM1VCEPNot applicable: ENIGMA says not to use PM1, and residue 1181 lies outside the defined RING 2-101, coiled-coil 1391-1424, and BRCT 1650-1857 domains.
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Reasoning
The ENIGMA BRCA1 specification explicitly says not to use PM1 and states that this evidence is considered as part of bioinformatic analysis. The variant is also outside the VCEP-defined BRCA1 functional domains: RING residues 2-101, coiled-coil residues 1391-1424, and BRCT repeats residues 1650-1857; residue 1181 is in none of these regions. No VCEP-approved hotspot route applies.
VCEP rule
Located in a mutational hot spot and/or critical and well-established functional domain. ... Do not use ... Considered as component of bioinformatic analysis (PP3/BP4).
Evidence considered
ENIGMA Specifications v1.2 Table 1: PM1 is marked 'Do not use' and is considered as a component of bioinformatic analysis (PP3/BP4).
ENIGMA functional-domain definition: BRCA1 RING aa 2-101, coiled-coil aa 1391-1424, and BRCA1 BRCT repeats aa 1650-1857.
The queried missense residue is Val1181, which is outside every VCEP-defined BRCA1 clinically important functional domain.
PM4VCEPNot applicable: the variant is missense, not an in-frame length change or stop-loss variant covered by PM4.
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Reasoning
NM_007294.4:c.3541G>A produces the missense substitution p.(Val1181Ile), with no in-frame insertion, in-frame deletion, delins, or stop-loss consequence. The ENIGMA BRCA1 VCEP explicitly instructs that PM4 is not used and treats the relevant protein-change assessment as part of bioinformatic analysis; this missense variant is outside the PM4 variant types named by the rule.
VCEP rule
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. ... Do not use
Evidence considered
Variant assessment: NM_007294.4:c.3541G>A is classified as missense and encodes p.(Val1181Ile); no protein-length-changing consequence is reported.
ENIGMA Specifications v1.2, Table 1, PM4 row: protein length changes are limited to in-frame deletions/insertions in a non-repeat region or stop-loss variants, and the specification says 'Do not use.'
PM5N/ANot applicable: ENIGMA does not use classic missense PM5, and c.3541G>A is a missense variant rather than a protein-termination-codon variant.
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Reasoning
The ENIGMA specification marks classic missense PM5 as not to be used and repurposes PM5 only for protein-termination-codon variants in specified exons. This variant is a missense substitution in exon 10, not a PTC or truncating variant, so neither classic same-residue PM5 nor PM5_PTC applies.
VCEP rule
Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. ... Do not use ... 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
ENIGMA Specifications v1.2: classic PM5 is marked 'Do not use'; the specification instead defines PM5_VariableWeight (PTC) for protein termination codons in an exon where a different proven pathogenic PTC has been seen.
Variant consequence evidence: NM_007294.4:c.3541G>A encodes p.Val1181Ile and is classified as missense, not PTC/truncating.
PM6VCEPNot applicable: ENIGMA says PM6 must not be used because BRCA1/2-related cancers are relatively common and de novo predictive capacity is uncalibrated.
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Reasoning
The ENIGMA BRCA1 specification explicitly states that PM6 is not to be used: confirmed de novo observations without confirmed paternity and maternity are uncalibrated because BRCA1/2-related cancers occur relatively commonly.
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 specification v1.2, Table 1, PM6: the criterion is marked Do not use for confirmed de novo observations without paternity and maternity confirmation.
PP2VCEPNot applicable: ENIGMA says not to use PP2 because BRCA1 has a high frequency of benign missense variants.
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Reasoning
The ENIGMA BRCA1 specification explicitly marks PP2 as not to be used because BRCA1 has a high frequency of benign missense variants. Therefore the missense mechanism and residue-level observations cannot activate PP2 under this VCEP.
VCEP rule
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. ... Do not use ... High frequency of benign missense variants.
Evidence considered
ENIGMA Specifications v1.2 Table 1: PP2 is marked 'Do not use' with the reason 'High frequency of benign missense variants.'
PP5VCEPNot applicable: the ENIGMA specification explicitly states Do not use PP5, regardless of the ClinVar expert-panel assertion.
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Reasoning
The ENIGMA specification explicitly says Do not use PP5. Although ClinVar records this variant as benign with an expert-panel review status, that reputable-source assertion cannot be applied as PP5 under this VCEP rule.
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
ClinVar variation 54911 identifies NM_007294.4(BRCA1):c.3541G>A (p.Val1181Ile) as benign with reviewed-by-expert-panel status.
The VCEP specification's PP5 entry states Do not use, so the ClinVar assertion is not applied to PP5.
BP2VCEPNot applicable: the ENIGMA BRCA1 specification says BP2 is not used and is applied only in the context of BS2.
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Reasoning
The ENIGMA BRCA1 specification explicitly says not to use BP2 and states that it is applied only in the context of BS2. BP2 is therefore not applicable under this governing VCEP, regardless of any trans, cis, or co-occurrence observations.
VCEP rule
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder, or observed in cis with a pathogenic variant in any inheritance pattern
Do not use
Applied only in the context of BS2.
Evidence considered
Specifications_V1.2_2024-11-18.docx.txt, BP2 section: the criterion describes observation in trans with a pathogenic variant or in cis with a pathogenic variant, then states 'Do not use' and 'Applied only in the context of BS2.'
Still missing
The governing file Specifications_V1.2_2024-11-18.docx.txt was searched for c.3541G>A, p.Val1181Ile, and p.V1181I; no variant-specific BP2 entry was found.
BP3VCEPNot applicable: BP3 is limited to in-frame deletions or insertions in repetitive regions without known function, not missense substitutions.
Details ▾Hide ▴
Reasoning
NM_007294.4:c.3541G>A is a missense substitution, not an in-frame deletion or insertion in a repetitive region without a known function. The ENIGMA BRCA1 VCEP explicitly says BP3 is not used and that this evidence is captured through bioinformatic tool prediction and domain analysis; the named BP3 variant type is absent here.
VCEP rule
In-frame deletions/insertions in a repetitive region without a known function ... Do not use
Evidence considered
Variant assessment: NM_007294.4:c.3541G>A is classified as missense and encodes p.(Val1181Ile); it is not an in-frame insertion or deletion.
ENIGMA Specifications v1.2, Table 1, BP3 row: BP3 is defined for in-frame deletions/insertions in a repetitive region without a known function, followed by the instruction 'Do not use.'
BP4N/ANot applicable: p.Val1181Ile is outside the VCEP-defined BRCA1 clinically important functional domains required for the BP4 missense path.
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Reasoning
The VCEP BP4 missense path is limited to missense or in-frame variants inside a potentially clinically important functional domain with no predicted protein or splice impact. p.Val1181Ile is outside the VCEP-defined BRCA1 clinically important domains, so BP4 is not applicable upstream of evaluating the BayesDel and SpliceAI benign thresholds.
VCEP rule
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
ClinGen ENIGMA BRCA1 specification v1.2: BP4 applies to missense or in-frame insertion, deletion or delins variants inside a potentially clinically important functional domain with no predicted protein or splicing impact.
ClinGen ENIGMA BRCA1 specification v1.2 defines clinically important BRCA1 domains as RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857; residue 1181 is outside these domains.
AF 4.5e-05 · 73 / 1,614,060 alleles · 1 hom · FAF 0.00019
South Asian25 / 91,076
0.000271 hom
Remaining individuals4 / 62,500
6.4e-05
East Asian2 / 44,876
4.5e-05
Admixed American2 / 60,010
3.3e-05
European (non-Finnish)38 / 1,180,010
3.2e-05
African/African American2 / 75,028
2.7e-05
0 alternate alleles recorded in 4 other groups: European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish.
gnomAD v2.1
AF 7.6e-05 · 19 / 251,184 alleles · 1 hom · FAF 0.00028
South Asian14 / 30,608
0.000461 hom
African/African American2 / 16,250
0.00012
Admixed American2 / 34,568
5.8e-05
European (non-Finnish)1 / 113,594
8.8e-06
0 alternate alleles recorded in 4 other groups: Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 4.52276e-05; MAF= 0.00452%, 73/1614060 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.000274496; MAF= 0.02745%, 25/91076 alleles, homozygotes = 1); grpmax FAF= 0.00018988.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.56418e-05; MAF= 0.00756%, 19/251184 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.000457397; MAF= 0.04574%, 14/30608 alleles, homozygotes = 1); grpmax FAF= 0.00027594.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
SpliceAI acceptor lossat -357 bp
0.003
SpliceAI acceptor gainat -180 bp
0.000
SpliceAI donor lossat -278 bp
0.001
SpliceAI donor gainat -153 bp
0.001
Pangolin splice lossmagnitude shown
-0.013
Pangolin splice gain
0.001
Other predictors
REVEL
0.376
BayesDel
-0.241
How the predictions were used
PP3VCEPNot met: SpliceAI maximum delta score 0.003 is below the VCEP PP3 splice-impact threshold of 0.2.
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Reasoning
The variant is a missense substitution, so the VCEP's PP3 splice-prediction path applies irrespective of functional-domain location. The governing threshold is SpliceAI >=0.2; the available SpliceAI result has a maximum delta score of 0.003, below that threshold. The PP3 protein-impact path is not applicable because p.Val1181Ile is at residue 1181, outside the VCEP-defined BRCA1 clinically important domains (RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857).
VCEP rule
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
ClinGen ENIGMA BRCA1 specification v1.2: PP3 applies to predicted splicing with SpliceAI >=0.2 for silent and missense/in-frame variants irrespective of location in a clinically important functional domain.
Case SpliceAI result for NM_007294.4:c.3541G>A (NP_009225.1:p.(Val1181Ile)): DS_AG 0.000, DS_AL 0.003, DS_DG 0.001, DS_DL 0.001; maximum delta score 0.003.
ClinGen ENIGMA BRCA1 specification v1.2 defines clinically important BRCA1 domains as RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857; residue 1181 is outside these domains, so the PP3 protein-impact BayesDel path does not apply.
BP7VCEPNot assessed: BP7_Strong (RNA) could cover this out-of-domain missense variant, but no qualifying mRNA-only assay result is available.
Details ▾Hide ▴
Reasoning
The ordinary BP7 path is for silent or deeper intronic variants and therefore does not apply to this missense variant. However, the VCEP expressly repurposes BP7 as BP7_Strong (RNA) for missense variants outside a clinically important functional domain when well-established mRNA-only functional studies show no damaging effect. The variant is outside the defined domains, but no qualifying mRNA-only assay result is available in the reviewed case evidence, so this RNA-specific path cannot be assessed.
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
ClinGen ENIGMA BRCA1 specification v1.2: BP7 is ordinarily applied to silent variants inside a potentially clinically important functional domain if BP4 is met, or to intronic variants outside conserved donor or acceptor motif positions if BP4 is met.
ClinGen ENIGMA BRCA1 specification v1.2 separately states that BP7_Strong (RNA) applies to intronic, silent, and missense/in-frame variants located outside a potentially clinically important functional domain when well-established in vitro or in vivo functional studies show no damaging effect as measured by an mRNA-only assay.
p.Val1181Ile is outside the VCEP-defined BRCA1 clinically important domains, but the reviewed case evidence contains no qualifying mRNA-only functional assay result for this variant.
Still missing
No well-established mRNA-only functional assay result demonstrating no damaging effect was available for NM_007294.4:c.3541G>A; without it, the VCEP BP7_Strong (RNA) path cannot be evaluated.
BP4N/ANot applicable: p.Val1181Ile is outside the VCEP-defined BRCA1 clinically important functional domains required for the BP4 missense path.
Details ▾Hide ▴
Reasoning
The VCEP BP4 missense path is limited to missense or in-frame variants inside a potentially clinically important functional domain with no predicted protein or splice impact. p.Val1181Ile is outside the VCEP-defined BRCA1 clinically important domains, so BP4 is not applicable upstream of evaluating the BayesDel and SpliceAI benign thresholds.
VCEP rule
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
ClinGen ENIGMA BRCA1 specification v1.2: BP4 applies to missense or in-frame insertion, deletion or delins variants inside a potentially clinically important functional domain with no predicted protein or splicing impact.
ClinGen ENIGMA BRCA1 specification v1.2 defines clinically important BRCA1 domains as RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857; residue 1181 is outside these domains.
Application of embryonic lethal or other obvious phenotypes to characterize the clinical significance of genetic variants found in trans with known deleterious mutations.
Judkins T et al. · 2005
Judkins et al. list BRCA1 V1181I as a variant of uncertain clinical significance associated with haplotypes 1 and 2; the paper does not provide a pathogenic or likely pathogenic same-amino-acid comparator or variant-specific functional result.
Table 3, variant list associated with more than one haplotype
Comprehensive genetic characterization of hereditary breast/ovarian cancer families from Slovakia.
Konecny M et al. · 2011
Konecny et al. report p.Val1181Ile under coding notation c.3524G>A, distinct from the queried c.3541G>A, as a missense variant of uncertain clinical significance in exon 11; computational predictions were benign or neutral and no variant-specific functional or segregation evidence was reported.
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.
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= 4.52276e-05; MAF= 0.00452%, 73/1614060 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.000274496; MAF= 0.02745%, 25/91076 alleles, homozygotes = 1); grpmax FAF= 0.00018988.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.56418e-05; MAF= 0.00756%, 19/251184 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.000457397; MAF= 0.04574%, 14/30608 alleles, homozygotes = 1); grpmax FAF= 0.00027594.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Likely benign (6 clinical laboratories) and as Uncertain significance (3 clinical laboratories) and as Benign (3 clinical laboratories) and as Likely Benign (1 clinical laboratory) and as Benign by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel). (ClinVarID = 54911)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.376. BayesDel score = -0.240503.
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 previously been reported in somatic cancers (COSMIC; COSV105897766, n = 3 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.