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BRCA1c.686C>TUncertain significance
Print report
Variant interpretation report

BRCA1 c.686C>T, p.Ser229Phe

NM_007294.4:c.686C>T NP_009225.1:p.(Ser229Phe) Missense · exon 10 View identifiers
Classification
Uncertain significance

Variant description:

The BRCA1 NM_007294.4:c.686C>T (NP_009225.1:p.(Ser229Phe)) missense variant has not previously been reported in somatic cancers (COSMIC). Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS).

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

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About 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.

NCBI Gene ↗ OncoKB ↗
LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is ClinGen 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.

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

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 1
BP1Strong
BP1 · strong

Met at strong: p.Ser229Phe lies outside ENIGMA domains and SpliceAI max delta 0.045 meets the ≤0.1 no-splicing threshold.

Recorded classification: Uncertain significance

VUS: BP1 (strong) is the only met criterion and does not satisfy an ENIGMA benign combination without additional benign evidence.

02The sources

Evidence at a glance

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

gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

No listed criterion applied
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
No screenshot for this evidence
REVEL score
0.659 recorded score

Recorded REVEL score: 0.659. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied
ClinVar submissions
2 reported laboratory submissions

2 Uncertain significance. ClinVar API review status: criteria provided, conflicting classifications.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA1, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

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

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen BRCA1 VCEP v1.2, with the data and sources behind each one.

28 criteria with recorded statuses: 1 met · 4 not met · 10 not assessed · 13 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

For the requested codon/residue/domain criteria, the ENIGMA VCEP supports BP1_Strong only: p.Ser229Phe is outside the defined critical domains and SpliceAI max delta is 0.045.

PS1 is not met because no qualifying pathogenic same-amino-acid reference variant was identified; PM1, PM5, and PP2 are not applicable under the VCEP's explicit restrictions.

PS4 cannot be assessed because no qualifying matched case-control enrichment statistics are available.

PP4 and BP5 cannot be assessed because the governing BRCA1 clinical-history table has no row for this variant and no combined clinical LR is available.

PP5 and BP6 are not applicable because the ENIGMA VCEP specification explicitly says Do not use for both criteria.

The ENIGMA VCEP scope makes PP3 potentially applicable only through the missense splicing path here; the measured SpliceAI maximum delta is below threshold, so PP3 is not met.

BP4 and BP7 are not applicable because this is a missense substitution outside the VCEP-defined functional-domain and variant-type scopes for those criteria.

Met · 1

BP1 StrongVCEPMet at strong: p.Ser229Phe lies outside ENIGMA domains and SpliceAI max delta 0.045 meets the ≤0.1 no-splicing threshold. Details ▾Hide ▴
Reasoning

NM_007294.4:c.686C>T is a missense variant encoding p.Ser229Phe. Residue 229 is outside all ENIGMA-defined potentially clinically important BRCA1 domains: RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857. SpliceAI predicts no significant splice impact, with maximum delta score 0.045, which is at or below the VCEP threshold of 0.1. The VCEP rule therefore supports BP1_Strong; missense prediction is explicitly not applicable on this path.

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. As justified in the appendices, (potentially) clinically important functional domains are defined as: BRCA1 RING aa 2-101; BRCA1 coiled-coil aa 1391-1424; BRCA1 BRCT repeats aa 1650-1857.
Evidence considered
  • Case normalization identifies p.Ser229Phe at residue 229; this is outside RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857.
  • Case SpliceAI result: maximum delta score 0.045, with DS_DL 0.045 and all other delta scores ≤0.012.
  • Specifications Table 1 and Appendix J define BP1_Strong for missense variants outside a potentially clinically important domain with SpliceAI ≤0.1; missense prediction is not applicable.
Sources
cspec ↗

Not met · 4 · evaluated, threshold not reached

PS1 VCEPNot met: no previously classified pathogenic variant with the same p.Ser229Phe amino-acid change was identified, despite SpliceAI max delta 0.045. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, NM_007294.4:c.686C>T (p.Ser229Phe/p.S229F), but no previously classified pathogenic variant producing the same amino-acid change was identified. The ENIGMA specification permits PS1 for a missense substitution only when such a previously classified pathogenic reference variant acts through protein change with no confirmed or predicted splicing effect; the available case evidence gives SpliceAI max delta 0.045, but no qualifying same-amino-acid pathogenic reference variant is available. The VCEP files were searched for c.686C>T, p.Ser229Phe, and p.S229F without a matching entry.

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)).
Evidence considered
  • Case normalization identifies NM_007294.4:c.686C>T as NP_009225.1:p.(Ser229Phe), also p.(S229F).
  • Case SpliceAI result: DS_AG 0.0, DS_AL 0.012, DS_DG 0.0, DS_DL 0.045; maximum delta score 0.045.
  • No qualifying same-amino-acid pathogenic reference variant was found in the searched ENIGMA VCEP materials.
Still missing
  • No c.686C>T, p.Ser229Phe, or p.S229F entry found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • No c.686C>T, p.Ser229Phe, or p.S229F entry found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No c.686C>T, p.Ser229Phe, or p.S229F entry found in Specifications_V1.2_2024-11-18.docx.txt.
  • No c.686C>T, p.Ser229Phe, or p.S229F entry found in Appendices_V1.2_2024-11-18.docx.txt.
Sources
cspec ↗
PP3 VCEPNot met: SpliceAI maximum delta 0.045 is below the ENIGMA PP3 splicing threshold of 0.2, and BayesDel 0.247749 is below the 0.28 protein-impact threshold. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, p.Ser229Phe, and lies outside the ENIGMA BRCA1 clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857). Therefore the protein-change PP3 path does not apply. The missense splicing path does apply irrespective of functional-domain location, but the available SpliceAI result has a maximum delta score of 0.045 (reported as 0.04), below the VCEP threshold of >=0.2. BayesDel no-AF is 0.247749, also below the BRCA1 protein-impact threshold of >=0.28, and cannot independently establish PP3 because the missense protein path requires a variant inside a clinically important functional domain. No governing VCEP table supplied a variant-specific pre-assigned PP3 code.

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 donor and acceptor ±1,2 positions.
Evidence considered
  • ENIGMA BRCA1 specification v1.2, Table 1 PP3 rule: the protein-impact path is limited to missense or in-frame variants inside a potentially clinically important functional domain with BayesDel no-AF >=0.28; the splicing path applies to silent and missense/in-frame variants irrespective of domain location when SpliceAI >=0.2.
  • SpliceAI Lookup for NM_007294.4:c.686C>T: DS_AG=0.0, DS_AL=0.012, DS_DG=0.0, DS_DL=0.045; maximum delta score=0.045, reported summary max delta score=0.04.
  • Local BayesDel no-AF lookup for BRCA1 c.686C>T (p.Ser229Phe): score=0.247749, below the VCEP BRCA1 PP3 threshold of 0.28.
  • The variant is missense p.Ser229Phe at amino acid 229; the VCEP-defined BRCA1 domains are RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857.
Still missing
  • No variant-specific entry for c.686C>T, p.Ser229Phe, or p.S229F was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No variant-specific entry for c.686C>T, p.Ser229Phe, or p.S229F was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No variant-specific entry for c.686C>T, p.Ser229Phe, or p.S229F was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No variant-specific entry for c.686C>T, p.Ser229Phe, or p.S229F was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗spliceai ↗bayesdel
BA1 VCEPNot met: the variant is absent from both specified non-cancer gnomAD datasets, so no filter allele frequency above 0.001 is available for BA1. Details ▾Hide ▴
Reasoning

The governing ENIGMA rule requires filter allele frequency above 0.001 in a specified non-founder population. The case evidence reports the variant absent from both gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, so no frequency above 0.001 is present to meet BA1. The VCEP supplementary tables, Specifications document, Appendices, and HUMU-40-1557-s001 were searched for c.686C>T, p.Ser229Phe, and p.S229F; no variant-specific entry was found in those files.

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
  • GNOMAD_V2_1_NON_CANCER: absent; search_status=absent and found=false for 17-41246862-G-A.
  • GNOMAD_V3_1_NON_CANCER: absent; search_status=absent and found=false for 17-43094845-G-A.
  • Specifications V1.2, benign stand-alone criterion BA1: filter allele frequency above 0.1% (FAF > 0.001) in gnomAD v2.1 non-cancer exome-only and/or gnomAD v3.1 non-cancer non-founder populations.
  • Appendix G: BA1 is based on the highest filter allele frequency in a non-founder gnomAD population, with exome and genome data assessed separately.
Still missing
  • No variant-specific entry for c.686C>T, p.Ser229Phe, or p.S229F was found in Specifications_V1.2_2024-11-18.docx.
  • No variant-specific entry for c.686C>T, p.Ser229Phe, or p.S229F was found in Appendices_V1.2_2024-11-18.docx.
  • No variant-specific entry for c.686C>T, p.Ser229Phe, or p.S229F was found in SupplementaryTables_V1.2_2024-11-18.xlsx.
  • No variant-specific entry for c.686C>T, p.Ser229Phe, or p.S229F was found in HUMU-40-1557-s001.xlsx.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗vcep_appendices_v1_2_2024_11_18 ↗
BS1 VCEPNot met: the variant is absent from both specified non-cancer gnomAD datasets, so no FAF above 0.00002 supports BS1. Details ▾Hide ▴
Reasoning

The governing ENIGMA rule requires FAF above 0.0001 for BS1 Strong or above 0.00002 through 0.0001 for BS1 Supporting. The case evidence reports the variant absent from both specified non-cancer gnomAD datasets, so neither frequency interval is met. The VCEP Specifications document and Appendices were searched for c.686C>T, p.Ser229Phe, and p.S229F; no variant-specific entry was 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
  • GNOMAD_V2_1_NON_CANCER: absent; search_status=absent and found=false for 17-41246862-G-A.
  • GNOMAD_V3_1_NON_CANCER: absent; search_status=absent and found=false for 17-43094845-G-A.
  • Specifications V1.2, BS1: BS1 Strong requires FAF > 0.0001; BS1 Supporting requires FAF > 0.00002 and FAF <= 0.0001 in the specified non-founder gnomAD populations.
  • Appendix G: BS1 uses the highest filter allele frequency in a non-founder gnomAD population, assessing exome and genome data separately.
Still missing
  • No variant-specific entry for c.686C>T, p.Ser229Phe, or p.S229F was found in Specifications_V1.2_2024-11-18.docx.
  • No variant-specific entry for c.686C>T, p.Ser229Phe, or p.S229F was found in Appendices_V1.2_2024-11-18.docx.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗vcep_appendices_v1_2_2024_11_18 ↗

Not assessed · 10 · no assessment recorded

PS3 VCEPNot assessed: ENIGMA Table 9 and supplementary ST4 contain no matching c.686C>T, p.Ser229Phe, or p.S229F functional-assay entry. Details ▾Hide ▴
Reasoning

PS3 cannot be assessed because the governing ENIGMA functional-assay sources contain no entry for NM_007294.4:c.686C>T, p.(Ser229Phe), or p.(S229F). The required Table 9 lookup returned no matching notation, and the supplementary ST4 functional dataset likewise returned no matching variant. No variant-specific validated protein assay result, assay-control result, calibrated code assignment, or usable functional publication finding was available in the case materials. The VCEP therefore provides insufficient evidence to determine whether a damaging functional effect is present or to assign PS3 strength.

VCEP rule
Well-established in vitro or in vivo functional studies supportive of a damaging effect Assay measures effect via protein only OR mRNA and protein combined. See Table 9, provided as a separate excel spreadsheet, for a comprehensive table of applicable codes using published calibrated functional assay results.
Evidence considered
  • Specifications_Table9_V1.2_2024-11-18.xlsx.txt: searched c.686C>T, p.Ser229Phe, and p.S229F; no matching row or pre-assigned PS3 code was found.
  • SupplementaryTables_V1.2_2024-11-18.xlsx.txt: searched c.686C>T, p.Ser229Phe, and p.S229F, including ST4; no matching functional-assay row was found.
  • Specifications_V1.2_2024-11-18.docx.txt and Appendices_V1.2_2024-11-18.docx.txt: governing PS3 rules require well-established damaging functional evidence and direct users to calibrated Table 9 results; no variant-specific result was identified.
  • HUMU-40-1557-s001.xlsx.txt: searched c.686C>T, p.Ser229Phe, and p.S229F; no matching variant row was found.
Still missing
  • No matching c.686C>T, p.Ser229Phe, or p.S229F entry was found in Specifications_Table9_V1.2_2024-11-18.xlsx.txt.
  • No matching c.686C>T, p.Ser229Phe, or p.S229F entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt, including the ST4 functional assay dataset.
  • No matching c.686C>T, p.Ser229Phe, or p.S229F entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No matching c.686C>T, p.Ser229Phe, or p.S229F entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No matching c.686C>T, p.Ser229Phe, or p.S229F entry was found in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_specifications_table9_v1_2_2024_11_18 ↗vcep_supplementarytables_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗vcep_humu_40_1557_s001 ↗
PS4 VCEPNot assessed: no qualifying matched case-control p-value, OR, or confidence interval is available for c.686C>T. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 specification requires case-control evidence with p-value ≤0.05 and OR ≥4, with the lower confidence interval excluding 2.0; it also requires ethnicity- and country-matched case and control datasets and says not to use proband counting as originally described. The available case evidence contains no qualifying case-control p-value, odds ratio, confidence interval, or matched dataset for NM_007294.4:c.686C>T (p.Ser229Phe; p.S229F). Therefore PS4 cannot be assessed 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. ... Do not use Proband Counting as originally described.
Evidence considered
  • ENIGMA Specifications v1.2, PS4: case-control studies require p-value ≤0.05 and OR ≥4, with the lower confidence interval excluding 2.0.
  • ENIGMA Specifications v1.2, PS4: the case dataset should be ethnicity and country-matched to the control dataset, and proband counting should not be used as originally described.
  • The case-evidence bundle contains no variant-specific case-control p-value, OR, confidence interval, or matched case-control dataset for NM_007294.4:c.686C>T (p.Ser229Phe; p.S229F).
Still missing
  • No case-control study result with p-value, OR, and confidence interval was available for NM_007294.4:c.686C>T / p.Ser229Phe / p.S229F.
  • The ENIGMA specification file was searched for c.686C>T, p.Ser229Phe, and p.S229F; no variant-specific entry was found.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
PM2 VCEPNot assessed: the variant is absent from both specified gnomAD datasets, but the required regional average read depth >=25 is unavailable. Details ▾Hide ▴
Reasoning

The variant is reported absent from the governing non-cancer gnomAD v2.1 exome-only and v3.1 genome datasets, satisfying the absence component of the ENIGMA PM2 rule. However, the rule also requires average read depth at the region to be at least 25, and the available records provide no read-depth value. PM2 therefore cannot be assessed without that quality metric. The VCEP Supplementary Tables, Specifications document, Appendices, and HUMU-40-1557-s001 were searched for c.686C>T, p.Ser229Phe, and p.S229F; no variant-specific entry was 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
  • GNOMAD_V2_1_NON_CANCER: absent; search_status=absent and found=false for 17-41246862-G-A.
  • GNOMAD_V3_1_NON_CANCER: absent; search_status=absent and found=false for 17-43094845-G-A.
  • Specifications V1.2, PM2 Supporting: absent from controls in gnomAD v2.1 non-cancer exome-only and gnomAD v3.1 non-cancer, with average read depth >=25 required.
  • Appendix G: PM2 Supporting recommends read depth >25 and excludes data that failed quality control; no read-depth value is provided for this variant.
Still missing
  • Regional average read depth for the variant in the governing gnomAD datasets is not reported.
  • No variant-specific entry for c.686C>T, p.Ser229Phe, or p.S229F was found in Specifications_V1.2_2024-11-18.docx.
  • No variant-specific entry for c.686C>T, p.Ser229Phe, or p.S229F was found in Appendices_V1.2_2024-11-18.docx.
  • No variant-specific entry for c.686C>T, p.Ser229Phe, or p.S229F was found in SupplementaryTables_V1.2_2024-11-18.xlsx.
  • No variant-specific entry for c.686C>T, p.Ser229Phe, or p.S229F was found in HUMU-40-1557-s001.xlsx.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗vcep_appendices_v1_2_2024_11_18 ↗vcep_supplementarytables_v1_2_2024_11_18 ↗vcep_humu_40_1557_s001 ↗
PM3 VCEPNot assessed: no Fanconi Anemia phenotype, co-occurring BRCA1 pathogenic variant, affected proband, or phase information is available for PM3 point assignment. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 v1.2 PM3 rule requires a patient with a phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia and a co-occurrent variant in the same gene, with points assigned according to phase and phenotype. The available case evidence contains no affected-proband observation, Fanconi Anemia phenotype, chromosome-breakage result, second BRCA1 pathogenic/likely pathogenic variant, or phase information for NM_007294.4:c.686C>T (p.Ser229Phe; p.S229F). Therefore PM3 cannot be assessed and no strength can be assigned.

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 BRCA1 specification v1.2, PM3 rule: application requires a patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia and co-occurrent variants in the same gene.
  • ENIGMA BRCA1 specification v1.2, Table 6: P or LP in trans or homozygote with a phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia contributes 2 points; phase unknown contributes 1 point; final PM3 strength is based on summed points.
  • Case evidence for NM_007294.4:c.686C>T (p.Ser229Phe; p.S229F) contains no affected-proband Fanconi Anemia presentation, chromosome-breakage result, second BRCA1 pathogenic/likely pathogenic variant, or phase observation.
Still missing
  • No affected-proband or Fanconi Anemia phenotype data, chromosome-breakage result, co-occurring BRCA1 pathogenic/likely pathogenic variant, or phase information was available in the case evidence bundle.
  • No matching c.686C>T, p.Ser229Phe, or p.S229F entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No matching c.686C>T, p.Ser229Phe, or p.S229F entry was found in HUMU-40-1557-s001.xlsx.txt.
  • No matching c.686C>T, p.Ser229Phe, or p.S229F entry was found in PMID_17924331_Easton_2007_AJHG.pdf.txt.
  • No matching c.686C>T, p.Ser229Phe, or p.S229F entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
  • No matching c.686C>T, p.Ser229Phe, or p.S229F entry was found in PMID_31853058_BRCA1_clinical_history_LR.xlsx.txt.
  • No matching c.686C>T, p.Ser229Phe, or p.S229F entry was found in PMID_31853058_Li_2020_GeneticsInMedicine.pdf.txt.
  • No matching c.686C>T, p.Ser229Phe, or p.S229F entry was found in PMID_31853058_methods_supplement.docx.txt.
  • No matching c.686C>T, p.Ser229Phe, or p.S229F entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • No matching c.686C>T, p.Ser229Phe, or p.S229F entry was found in Specifications_Table9_V1.2_2024-11-18.xlsx.txt.
  • No matching c.686C>T, p.Ser229Phe, or p.S229F entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No matching c.686C>T, p.Ser229Phe, or p.S229F entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
Sources
vcep_specifications_v1_2_2024_11_18 ↗
PP1 VCEPNot assessed: no affected-relative genotypes or quantitative co-segregation LR are available to compare with the VCEP PP1 supporting threshold of LR ≥2.08:1. Details ▾Hide ▴
Reasoning

PP1 requires co-segregation with disease in multiple affected family members measured by a quantitative co-segregation method and assigns strength from the resulting Bayes-score likelihood ratio. The available case evidence contains no proband-level segregation observations, parental testing, meioses, affected-relative genotypes, or quantitative co-segregation LR for NM_007294.4:c.686C>T (p.Ser229Phe/p.S229F). The VCEP full-text files Specifications_V1.2_2024-11-18.docx.txt and HUMU-40-1557-s001.xlsx.txt were searched for c.686C>T, p.Ser229Phe, and p.S229F; no variant-specific entry was found in either file.

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
  • The VCEP rule requires quantitative co-segregation in multiple affected family members and assigns PP1 Supporting at LR ≥2.08:1, Moderate at LR ≥4.3:1, Strong at LR ≥18.7:1, and Very Strong at LR ≥350:1.
  • No case-level segregation, parental, meiosis, or quantitative LR data for NM_007294.4:c.686C>T (p.Ser229Phe/p.S229F) is present in the supplied evidence.
  • Specifications_V1.2_2024-11-18.docx.txt was searched for c.686C>T, p.Ser229Phe, and p.S229F with no variant-specific entry found.
  • HUMU-40-1557-s001.xlsx.txt was searched for c.686C>T, p.Ser229Phe, and p.S229F with no variant-specific entry found.
Still missing
  • No proband-level segregation record, parental testing, affected-relative genotypes, meioses, or quantitative co-segregation LR is available for this variant.
  • No entry for c.686C>T, p.Ser229Phe, or p.S229F was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.686C>T, p.Ser229Phe, or p.S229F was found in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗
PP4 VCEPNot assessed: the governing clinical-history table has no c.686C>T row and no combined clinical LR is available. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 specification restricts PP4 to combined multifactorial clinical likelihood ratios and requires PP4 at supporting strength when LR ≥2.08:1, with higher strengths at LR ≥4.3:1, ≥18.7:1, and ≥350:1. The governing Li et al. 2020 BRCA1 clinical-history table was searched for c.686C>T, p.Ser229Phe, and p.S229F, but contains no row for this variant, and no combined clinical LR or other clinically calibrated LR components are available in the case evidence. PP4 is therefore not assessed.

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 ... PP4_Moderate – LR≥4.3:1 ... PP4_Strong – LR≥18.7:1 ... PP4_Very Strong – LR≥350:1
Evidence considered
  • ENIGMA Specifications v1.2, PP4: use only to capture combined LR towards pathogenicity based on multifactorial likelihood clinical data; PP4 supporting requires LR ≥2.08:1, PP4 moderate LR ≥4.3:1, PP4 strong LR ≥18.7:1, and PP4 very strong LR ≥350:1.
  • Li et al. 2020 Supplementary Table 3 BRCA1 clinical-history LR table, Sheet1: searches for BRCA1 c.686C>T, p.Ser229Phe, and p.S229F found no matching row.
  • No combined clinical LR or calibrated clinical-history component for this variant is present in the case evidence.
Still missing
  • PMID_31853058_BRCA1_clinical_history_LR.xlsx was searched for c.686C>T, p.Ser229Phe, and p.S229F; no entry was found.
  • No combined multifactorial clinical LR or sufficient calibrated component LRs are available for this variant.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_pmid_31853058_brca1_clinical_history_lr ↗PMID:31853058 ↗
BS2 VCEPNot assessed: no phenotyped cohort observation, homozygote, phase, or age/follow-up evidence is available for the BS2 point system. Details ▾Hide ▴
Reasoning

The ENIGMA BS2 rule requires phenotyped clinical or research-cohort observations of the variant in trans with a pathogenic/likely pathogenic variant, as a homozygote, or with unknown phase, in a presumed Fanconi-Anemia-unaffected patient, followed by point assignment based on age or cancer follow-up. The available case evidence contains no such individual-level observation, homozygote count, phase information, or age/follow-up data. The Specifications document and Appendices were searched for c.686C>T, p.Ser229Phe, and p.S229F; no variant-specific entry was found.

VCEP rule
Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype. ... BS2 = 4 (or more) points; BS2_moderate = 2 points; BS2_Supporting = 1 point.
Evidence considered
  • Specifications V1.2, BS2: applied in the absence of features of recessive disease, namely Fanconi Anemia phenotype, using Table 8 points per proband.
  • Appendix H, Application of BS2: observations must be in trans with a P/LP variant or homozygous in a presumed FA-unaffected patient, with points based on age at cancer diagnosis or last follow-up.
  • Appendix H Table 13: BS2 points require patient first cancer onset or cancer-unaffected follow-up in the >50-year or 40-50-year categories; no such variant-specific data are available.
Still missing
  • No variant-specific entry for c.686C>T, p.Ser229Phe, or p.S229F was found in Specifications_V1.2_2024-11-18.docx.
  • No variant-specific entry for c.686C>T, p.Ser229Phe, or p.S229F was found in Appendices_V1.2_2024-11-18.docx.
  • Individual-level BS2 observations with phase, homozygote status, Fanconi-Anemia phenotype assessment, and age at cancer diagnosis or last follow-up are unavailable.
Sources
cspec ↗vcep_appendices_v1_2_2024_11_18 ↗
BS3 VCEPNot assessed: ENIGMA Table 9 and supplementary ST4 contain no matching c.686C>T, p.Ser229Phe, or p.S229F functional-assay entry. Details ▾Hide ▴
Reasoning

BS3 cannot be assessed because the governing ENIGMA functional-assay sources contain no entry for NM_007294.4:c.686C>T, p.(Ser229Phe), or p.(S229F). The required Table 9 lookup returned no matching notation, and the supplementary ST4 functional dataset likewise returned no matching variant. No variant-specific validated assay showing no damaging effect, assay-control result, calibrated code assignment, or usable functional publication finding was available in the case materials. The VCEP therefore provides insufficient evidence to determine whether a benign functional effect is present or to assign BS3 strength.

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 Table 9, provided as a separate excel spreadsheet, for a comprehensive table of applicable codes using published calibrated functional assay results.
Evidence considered
  • Specifications_Table9_V1.2_2024-11-18.xlsx.txt: searched c.686C>T, p.Ser229Phe, and p.S229F; no matching row or pre-assigned BS3 code was found.
  • SupplementaryTables_V1.2_2024-11-18.xlsx.txt: searched c.686C>T, p.Ser229Phe, and p.S229F, including ST4; no matching functional-assay row was found.
  • Specifications_V1.2_2024-11-18.docx.txt and Appendices_V1.2_2024-11-18.docx.txt: governing BS3 rules require well-established evidence showing no damaging effect and direct users to calibrated Table 9 results; no variant-specific result was identified.
  • HUMU-40-1557-s001.xlsx.txt: searched c.686C>T, p.Ser229Phe, and p.S229F; no matching variant row was found.
Still missing
  • No matching c.686C>T, p.Ser229Phe, or p.S229F entry was found in Specifications_Table9_V1.2_2024-11-18.xlsx.txt.
  • No matching c.686C>T, p.Ser229Phe, or p.S229F entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt, including the ST4 functional assay dataset.
  • No matching c.686C>T, p.Ser229Phe, or p.S229F entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No matching c.686C>T, p.Ser229Phe, or p.S229F entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No matching c.686C>T, p.Ser229Phe, or p.S229F entry was found in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_specifications_table9_v1_2_2024_11_18 ↗vcep_supplementarytables_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗vcep_humu_40_1557_s001 ↗
BS4 VCEPNot assessed: no non-segregation observations or quantitative co-segregation LR are available to compare with the VCEP BS4 supporting threshold of LR ≤0.48:1. Details ▾Hide ▴
Reasoning

BS4 requires lack of segregation in affected family members measured by a quantitative co-segregation method and assigns benign strength from the resulting Bayes-score likelihood ratio. The available case evidence contains no affected-relative genotypes, non-segregation observations, parental testing, meioses, or quantitative co-segregation LR for NM_007294.4:c.686C>T (p.Ser229Phe/p.S229F). The VCEP full-text files Specifications_V1.2_2024-11-18.docx.txt and HUMU-40-1557-s001.xlsx.txt were searched for c.686C>T, p.Ser229Phe, and p.S229F; no variant-specific entry was found in either file.

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 ≤0.48:1 ... BS4_Moderate - LR ≤0.23:1 ... BS4 - LR ≤0.05:1 ... BS4_VeryStrong – LR ≤0.00285:1
Evidence considered
  • The VCEP rule requires quantitative assessment of lack of segregation in affected family members and assigns BS4 Supporting at LR ≤0.48:1, Moderate at LR ≤0.23:1, Strong at LR ≤0.05:1, and Very Strong at LR ≤0.00285:1.
  • No case-level non-segregation, affected-relative genotype, parental, meiosis, or quantitative LR data for NM_007294.4:c.686C>T (p.Ser229Phe/p.S229F) is present in the supplied evidence.
  • Specifications_V1.2_2024-11-18.docx.txt was searched for c.686C>T, p.Ser229Phe, and p.S229F with no variant-specific entry found.
  • HUMU-40-1557-s001.xlsx.txt was searched for c.686C>T, p.Ser229Phe, and p.S229F with no variant-specific entry found.
Still missing
  • No affected-relative non-segregation record, parental testing, meioses, or quantitative co-segregation LR is available for this variant.
  • No entry for c.686C>T, p.Ser229Phe, or p.S229F was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No entry for c.686C>T, p.Ser229Phe, or p.S229F was found in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗
BP5 VCEPNot assessed: no variant-specific combined LR is available to compare with the BP5 ≤0.48 threshold. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 specification restricts BP5 to combined multifactorial clinical likelihood ratios against pathogenicity. Its criterion-specific operators are LR ≤0.48 for supporting, LR ≤0.23 for moderate, LR ≤0.05 for strong, and LR ≤0.00285 for very strong, with LR >0.48 to 1.00 not informative. The governing Li et al. 2020 BRCA1 clinical-history table was searched for c.686C>T, p.Ser229Phe, and p.S229F, but contains no row for this variant; no combined clinical LR or calibrated benign-direction clinical evidence is available. BP5 is therefore not assessed, and no numeric comparison can be performed.

VCEP rule
Use ONLY to capture combined LR against pathogenicity, based on multifactorial likelihood clinical data. ... BP5_VeryStrong – LR ≤0.00285:1 ... BP5_Strong - LR ≤0.05:1 ... BP5_Moderate - LR ≤0.23:1 ... BP5 - LR ≤0.48 to >0.23:1 ... Combined LR >0.48-1.00 is not informative (BP5 not applicable)
Evidence considered
  • ENIGMA Specifications v1.2, BP5: use only to capture combined LR against pathogenicity based on multifactorial likelihood clinical data.
  • ENIGMA Specifications v1.2, BP5 thresholds: BP5 supporting LR ≤0.48 to >0.23:1; BP5 moderate LR ≤0.23:1; BP5 strong LR ≤0.05:1; BP5 very strong LR ≤0.00285:1.
  • Li et al. 2020 Supplementary Table 3 BRCA1 clinical-history LR table, Sheet1: searches for BRCA1 c.686C>T, p.Ser229Phe, and p.S229F found no matching row.
  • No combined clinical LR or calibrated benign-direction clinical-history component for this variant is present in the case evidence.
Still missing
  • PMID_31853058_BRCA1_clinical_history_LR.xlsx was searched for c.686C>T, p.Ser229Phe, and p.S229F; no entry was found.
  • No combined multifactorial clinical LR or sufficient calibrated component LRs are available for this variant.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_pmid_31853058_brca1_clinical_history_lr ↗PMID:31853058 ↗
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: c.686C>T is a missense substitution, whereas the VCEP PVS1 rule is limited to null variants. Details ▾Hide ▴
Reasoning

NM_007294.4:c.686C>T is a missense substitution, NP_009225.1:p.(Ser229Phe) (p.S229F), in exon 10. The ENIGMA BRCA1 VCEP PVS1 rule applies to null variants—nonsense, frameshift, canonical splice-site, initiation-codon, or exon-deletion variants—and therefore does not apply to this missense variant. The VCEP's Table 4 was searched for c.686C>T, p.Ser229Phe, and p.S229F; no entry was found, which is consistent with the table's null-variant/splice-site scope.

VCEP rule
Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
Evidence considered
  • Case normalization: NM_007294.4:c.686C>T; NP_009225.1:p.(Ser229Phe); NP_009225.1:p.(S229F); exon 10; consequence class missense.
  • ENIGMA BRCA1 VCEP PVS1 rule: null variant (nonsense, frameshift, canonical splice-site, initiation codon, or single/multi-exon deletion) in a gene where loss of function is a known disease mechanism.
  • The governing Table 4 and the three additional on-record VCEP files were searched under c.686C>T, p.Ser229Phe, and p.S229F; no exact variant entry was found.
Still missing
  • No c.686C>T, p.Ser229Phe, or p.S229F entry found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt; this file is the exon-level null-variant and canonical splice-site table.
  • No c.686C>T, p.Ser229Phe, or p.S229F entry found in Specifications_V1.2_2024-11-18.docx.txt.
  • No c.686C>T, p.Ser229Phe, or p.S229F entry found in Appendices_V1.2_2024-11-18.docx.txt.
  • No c.686C>T, p.Ser229Phe, or p.S229F entry found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18 ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗
PS2 VCEPNot applicable: the VCEP prohibits PS2 because BRCA1/2 cancers are relatively common and de novo predictive capacity is uncalibrated. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 VCEP explicitly marks PS2 as not applicable and states not to use it because BRCA1/2-related cancers occur relatively commonly and the predictive capacity of de novo occurrences has not been calibrated.

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
  • The VCEP CSPEC entry for PS2 specifies applicability as Not applicable and instructs Do not use.
Sources
cspec ↗
PM1 VCEPNot applicable: ENIGMA explicitly says PM1 is not used, regardless of residue 229 being outside its listed critical domains. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP explicitly instructs that PM1 is not used and is considered as part of the bioinformatic analysis under PP3/BP4. Although residue 229 is outside the VCEP-listed RING, coiled-coil, and BRCT domains, domain location cannot independently activate PM1 under this specification.

VCEP rule
Do not use ... Considered as component of bioinformatic analysis (PP3/BP4).
Evidence considered
  • Specifications Table 1 marks PM1 as Do not use and states it is considered as a component of bioinformatic analysis (PP3/BP4).
  • The VCEP-defined BRCA1 domains are RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857; p.Ser229Phe lies outside all three.
Sources
cspec ↗
PM4 VCEPNot applicable: p.(Ser229Phe) is a missense substitution with no protein-length change, and the VCEP directs that PM4 is not used. Details ▾Hide ▴
Reasoning

NM_007294.4:c.686C>T is a missense substitution producing p.(Ser229Phe), with no protein-length change, in-frame insertion/deletion, or stop-loss consequence. The ENIGMA BRCA1 VCEP explicitly directs that PM4 is not used and is instead captured through bioinformatic analysis; the criterion is therefore not applicable to this variant.

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 consequence: missense p.(Ser229Phe), not an in-frame deletion/insertion or stop-loss variant.
  • ENIGMA BRCA1 VCEP Table 1 states that PM4 protein-length changes are not used and are considered under bioinformatic analysis (PP3/BP4).
  • The governing VCEP files were searched under c.686C>T, p.Ser229Phe, and p.S229F; no exact variant entry was found.
Still missing
  • No c.686C>T, p.Ser229Phe, or p.S229F entry found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • No c.686C>T, p.Ser229Phe, or p.S229F entry found in Specifications_V1.2_2024-11-18.docx.txt.
  • No c.686C>T, p.Ser229Phe, or p.S229F entry found in Appendices_V1.2_2024-11-18.docx.txt.
  • No c.686C>T, p.Ser229Phe, or p.S229F entry found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗
PM5 N/ANot applicable: ENIGMA reserves PM5 for pathogenic PTC comparisons, whereas this variant is missense p.Ser229Phe. Details ▾Hide ▴
Reasoning

The classic missense PM5 criterion is marked Do not use by the ENIGMA VCEP. ENIGMA repurposes PM5 only for protein-termination-codon variants in an exon with a previously proven pathogenic PTC; this variant is missense p.Ser229Phe, not a PTC. No variant-specific entry was found in the searched ENIGMA files.

VCEP rule
Do not use ... Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before
Evidence considered
  • The case consequence is missense and the protein change is p.Ser229Phe/p.S229F, not a protein termination codon.
  • Specifications Table 1 marks classic PM5 as Do not use and separately defines PM5_VariableWeight (PTC) for genomic PTC changes.
Still missing
  • No c.686C>T, p.Ser229Phe, or p.S229F entry found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • No c.686C>T, p.Ser229Phe, or p.S229F entry found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No c.686C>T, p.Ser229Phe, or p.S229F entry found in Specifications_V1.2_2024-11-18.docx.txt.
  • No c.686C>T, p.Ser229Phe, or p.S229F entry found in Appendices_V1.2_2024-11-18.docx.txt.
Sources
cspec ↗
PM6 VCEPNot applicable: the VCEP prohibits PM6 because BRCA1/2 cancers are relatively common and de novo predictive capacity is uncalibrated. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 VCEP explicitly marks PM6 as not applicable and states not to use it because BRCA1/2-related cancers occur relatively commonly and the predictive capacity of de novo occurrences has not been calibrated.

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
  • The VCEP CSPEC entry for PM6 specifies applicability as Not applicable and instructs Do not use.
Sources
cspec ↗
PP2 VCEPNot applicable: ENIGMA says PP2 is not used because BRCA1 has a high frequency of benign missense variants. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP marks PP2 as Do not use because of the high frequency of benign missense variants. Therefore, the missense nature of p.Ser229Phe cannot activate PP2 under this VCEP framework.

VCEP rule
Do not use ... High frequency of benign missense variants.
Evidence considered
  • Specifications Table 1 lists PP2 as Do not use and gives the reason as high frequency of benign missense variants.
Sources
cspec ↗
PP5 VCEPNot applicable: the ENIGMA BRCA1 specification explicitly states that PP5 should not be used. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 specification explicitly states that PP5 is not to be used. No PP5 evidence can override that VCEP-specific applicability decision.

VCEP rule
Do not use
Evidence considered
  • ENIGMA Specifications v1.2, PP5: reputable-source reports of pathogenicity are designated Do not use.
  • The CSPEC PP5 entry states: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
BP2 VCEPNot applicable: the ENIGMA specification says BP2 is not to be used and applies it only in the context of BS2. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 v1.2 specification explicitly states that BP2 is not to be used and is applied only in the context of BS2. Therefore BP2 is not applicable regardless of whether an in-trans or in-cis pathogenic-variant observation exists.

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 BRCA1 specification v1.2, BP2 entry: 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; the next lines state: Do not use. Applied only in the context of BS2.
Still missing
  • No matching c.686C>T, p.Ser229Phe, or p.S229F entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No matching c.686C>T, p.Ser229Phe, or p.S229F entry was found in HUMU-40-1557-s001.xlsx.txt.
  • No matching c.686C>T, p.Ser229Phe, or p.S229F entry was found in PMID_17924331_Easton_2007_AJHG.pdf.txt.
  • No matching c.686C>T, p.Ser229Phe, or p.S229F entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
  • No matching c.686C>T, p.Ser229Phe, or p.S229F entry was found in PMID_31853058_BRCA1_clinical_history_LR.xlsx.txt.
  • No matching c.686C>T, p.Ser229Phe, or p.S229F entry was found in PMID_31853058_Li_2020_GeneticsInMedicine.pdf.txt.
  • No matching c.686C>T, p.Ser229Phe, or p.S229F entry was found in PMID_31853058_methods_supplement.docx.txt.
  • No matching c.686C>T, p.Ser229Phe, or p.S229F entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • No matching c.686C>T, p.Ser229Phe, or p.S229F entry was found in Specifications_Table9_V1.2_2024-11-18.xlsx.txt.
  • No matching c.686C>T, p.Ser229Phe, or p.S229F entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No matching c.686C>T, p.Ser229Phe, or p.S229F entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
Sources
vcep_specifications_v1_2_2024_11_18 ↗
BP3 VCEPNot applicable: p.(Ser229Phe) is not an in-frame deletion or insertion, the only variant type named by the VCEP BP3 rule. Details ▾Hide ▴
Reasoning

NM_007294.4:c.686C>T is a missense substitution producing p.(Ser229Phe), not an in-frame deletion or insertion. The ENIGMA BRCA1 VCEP specifies BP3 only for in-frame deletions/insertions in repetitive regions without known function and states that the code is not used; BP3 is therefore not applicable.

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.
Evidence considered
  • Case consequence: missense p.(Ser229Phe), not an in-frame deletion or insertion.
  • ENIGMA BRCA1 VCEP Table 1 states that BP3 concerns in-frame deletions/insertions in repetitive regions without known function and is not used.
  • The governing VCEP files were searched under c.686C>T, p.Ser229Phe, and p.S229F; no exact variant entry was found.
Still missing
  • No c.686C>T, p.Ser229Phe, or p.S229F entry found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • No c.686C>T, p.Ser229Phe, or p.S229F entry found in Specifications_V1.2_2024-11-18.docx.txt.
  • No c.686C>T, p.Ser229Phe, or p.S229F entry found in Appendices_V1.2_2024-11-18.docx.txt.
  • No c.686C>T, p.Ser229Phe, or p.S229F entry found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗
BP4 N/ANot applicable: p.Ser229Phe is a missense variant at residue 229, outside all ENIGMA-defined BRCA1 functional domains required for the BP4 missense path. Details ▾Hide ▴
Reasoning

BP4 is not applicable to this variant under the governing ENIGMA rule because the missense BP4 path is restricted to missense or in-frame variants inside a potentially clinically important functional domain. p.Ser229Phe is at amino acid 229, outside the defined BRCA1 RING, coiled-coil, and BRCT domains. The low SpliceAI score and intermediate BayesDel score therefore do not make BP4 applicable.

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
  • ENIGMA BRCA1 specification v1.2, Table 1 BP4 rule: the missense/in-frame BP4 path requires location inside a potentially clinically important functional domain and both BayesDel no-AF <=0.15 and SpliceAI <=0.1.
  • Variant consequence and location: NM_007294.4:c.686C>T, p.Ser229Phe, a missense substitution at residue 229; this is outside the VCEP-defined RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857.
Still missing
  • No variant-specific entry for c.686C>T, p.Ser229Phe, or p.S229F was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No variant-specific entry for c.686C>T, p.Ser229Phe, or p.S229F was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No variant-specific entry for c.686C>T, p.Ser229Phe, or p.S229F was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No variant-specific entry for c.686C>T, p.Ser229Phe, or p.S229F was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗
BP6 VCEPNot applicable: the ENIGMA BRCA1 specification explicitly states that BP6 should not be used. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 specification explicitly states that BP6 is not to be used. No BP6 evidence can override that VCEP-specific applicability decision.

VCEP rule
Do not use
Evidence considered
  • ENIGMA Specifications v1.2, BP6: reputable-source reports of benignity are designated Do not use.
  • The CSPEC BP6 entry states: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18 ↗
BP7 N/ANot applicable: BP7 covers silent or qualifying intronic variants, whereas c.686C>T produces the missense substitution p.Ser229Phe. Details ▾Hide ▴
Reasoning

BP7 is limited by the ENIGMA rule to silent variants and qualifying intronic variants, with BP4 met. This variant is missense, not silent or intronic, so BP7 is upstream not_applicable regardless of its SpliceAI score.

VCEP rule
Apply BP7 for Silent variant inside a (potentially) clinically important functional domain, IF BP4 met. Intronic variants located outside conserved donor or acceptor motif positions (at or beyond positions +7/-21) IF BP4 met
Evidence considered
  • ENIGMA BRCA1 specification v1.2, Table 1 BP7 rule: BP7 applies to silent variants inside a potentially clinically important functional domain if BP4 is met, or intronic variants outside conserved donor/acceptor motif positions if BP4 is met.
  • Variant consequence: NM_007294.4:c.686C>T produces the missense substitution p.Ser229Phe, so neither the silent-variant nor intronic-variant BP7 path applies.
Still missing
  • No variant-specific entry for c.686C>T, p.Ser229Phe, or p.S229F was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No variant-specific entry for c.686C>T, p.Ser229Phe, or p.S229F was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No variant-specific entry for c.686C>T, p.Ser229Phe, or p.S229F was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No variant-specific entry for c.686C>T, p.Ser229Phe, or p.S229F was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗

Identifiers

Gene
BRCA1
Transcript
NM_007294.4
Coding (HGVS c.)
NM_007294.4:c.686C>T
Protein (HGVS p.)
NP_009225.1:p.(Ser229Phe)
GRCh38
chr17:43094845 G>A
GRCh37
chr17:41246862 G>A
Location and type
Exon 10 · missense
ClinVar
4800830, 3634642, 1709638, 826675

Gene diagram

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…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +15 bp
0.012
SpliceAI acceptor gainat -101 bp
0.000
SpliceAI donor lossat -101 bp
0.045
SpliceAI donor gainat +15 bp
0.000
Pangolin splice lossmagnitude shown
-0.046
Pangolin splice gain
0.002

Other predictors

REVEL
0.659
BayesDel
0.248

How the predictions were used

PP3 VCEPNot met: SpliceAI maximum delta 0.045 is below the ENIGMA PP3 splicing threshold of 0.2, and BayesDel 0.247749 is below the 0.28 protein-impact threshold. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, p.Ser229Phe, and lies outside the ENIGMA BRCA1 clinically important functional domains (RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857). Therefore the protein-change PP3 path does not apply. The missense splicing path does apply irrespective of functional-domain location, but the available SpliceAI result has a maximum delta score of 0.045 (reported as 0.04), below the VCEP threshold of >=0.2. BayesDel no-AF is 0.247749, also below the BRCA1 protein-impact threshold of >=0.28, and cannot independently establish PP3 because the missense protein path requires a variant inside a clinically important functional domain. No governing VCEP table supplied a variant-specific pre-assigned PP3 code.

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 donor and acceptor ±1,2 positions.
Evidence considered
  • ENIGMA BRCA1 specification v1.2, Table 1 PP3 rule: the protein-impact path is limited to missense or in-frame variants inside a potentially clinically important functional domain with BayesDel no-AF >=0.28; the splicing path applies to silent and missense/in-frame variants irrespective of domain location when SpliceAI >=0.2.
  • SpliceAI Lookup for NM_007294.4:c.686C>T: DS_AG=0.0, DS_AL=0.012, DS_DG=0.0, DS_DL=0.045; maximum delta score=0.045, reported summary max delta score=0.04.
  • Local BayesDel no-AF lookup for BRCA1 c.686C>T (p.Ser229Phe): score=0.247749, below the VCEP BRCA1 PP3 threshold of 0.28.
  • The variant is missense p.Ser229Phe at amino acid 229; the VCEP-defined BRCA1 domains are RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857.
Still missing
  • No variant-specific entry for c.686C>T, p.Ser229Phe, or p.S229F was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No variant-specific entry for c.686C>T, p.Ser229Phe, or p.S229F was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No variant-specific entry for c.686C>T, p.Ser229Phe, or p.S229F was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No variant-specific entry for c.686C>T, p.Ser229Phe, or p.S229F was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗spliceai ↗bayesdel
BP4 N/ANot applicable: p.Ser229Phe is a missense variant at residue 229, outside all ENIGMA-defined BRCA1 functional domains required for the BP4 missense path. Details ▾Hide ▴
Reasoning

BP4 is not applicable to this variant under the governing ENIGMA rule because the missense BP4 path is restricted to missense or in-frame variants inside a potentially clinically important functional domain. p.Ser229Phe is at amino acid 229, outside the defined BRCA1 RING, coiled-coil, and BRCT domains. The low SpliceAI score and intermediate BayesDel score therefore do not make BP4 applicable.

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
  • ENIGMA BRCA1 specification v1.2, Table 1 BP4 rule: the missense/in-frame BP4 path requires location inside a potentially clinically important functional domain and both BayesDel no-AF <=0.15 and SpliceAI <=0.1.
  • Variant consequence and location: NM_007294.4:c.686C>T, p.Ser229Phe, a missense substitution at residue 229; this is outside the VCEP-defined RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857.
Still missing
  • No variant-specific entry for c.686C>T, p.Ser229Phe, or p.S229F was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No variant-specific entry for c.686C>T, p.Ser229Phe, or p.S229F was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No variant-specific entry for c.686C>T, p.Ser229Phe, or p.S229F was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No variant-specific entry for c.686C>T, p.Ser229Phe, or p.S229F was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗
BP7 N/ANot applicable: BP7 covers silent or qualifying intronic variants, whereas c.686C>T produces the missense substitution p.Ser229Phe. Details ▾Hide ▴
Reasoning

BP7 is limited by the ENIGMA rule to silent variants and qualifying intronic variants, with BP4 met. This variant is missense, not silent or intronic, so BP7 is upstream not_applicable regardless of its SpliceAI score.

VCEP rule
Apply BP7 for Silent variant inside a (potentially) clinically important functional domain, IF BP4 met. Intronic variants located outside conserved donor or acceptor motif positions (at or beyond positions +7/-21) IF BP4 met
Evidence considered
  • ENIGMA BRCA1 specification v1.2, Table 1 BP7 rule: BP7 applies to silent variants inside a potentially clinically important functional domain if BP4 is met, or intronic variants outside conserved donor/acceptor motif positions if BP4 is met.
  • Variant consequence: NM_007294.4:c.686C>T produces the missense substitution p.Ser229Phe, so neither the silent-variant nor intronic-variant BP7 path applies.
Still missing
  • No variant-specific entry for c.686C>T, p.Ser229Phe, or p.S229F was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No variant-specific entry for c.686C>T, p.Ser229Phe, or p.S229F was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No variant-specific entry for c.686C>T, p.Ser229Phe, or p.S229F was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No variant-specific entry for c.686C>T, p.Ser229Phe, or p.S229F was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.659. BayesDel score = 0.247749.

6 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

  • Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots".
    Dines JN et al. · 2020
    This paper does not explicitly mention BRCA1 c.686C>T or p.Ser229Phe. It characterizes BRCA1 exon 11, which includes residue 229, as a missense-variant coldspot and reports no confirmed pathogenic or likely pathogenic missense variants in the analyzed exon 11 region, but this study's coldspot framework was not used to override ENIGMA's explicit PM1 and PP2 restrictions.
    Does not name this variant
    PMID 31911673 ↗
    Quoted passage
    By contrast, exon 11 accounts for ~60% of the coding sequence but has no confirmed P + LP missense variants, and 58.0% (69/119) of B + LB variants. The estimated odds ratio for pathogenicity of missense variants in exon 11 is <0.01 (95% confidence interval [CI] 0.0–0.01, which satisfies the criteria for “strong benign” evidence, Table 2).18 Therefore, we classify this region as a coldspot.

    Results, BRCA1 section; Table 1 and Table 2

  • American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility.
    American Society of Clinical Oncology · 2003
    No paper-specific finding is recorded.
    PMID 12692171 ↗
  • Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.
    Berliner JL et al. · 2007
    No paper-specific finding is recorded.
    PMID 17508274 ↗
  • The emerging landscape of breast cancer susceptibility.
    Stratton MR et al. · 2008
    No paper-specific finding is recorded.
    PMID 18163131 ↗
  • Summaries for patients. Assessing the genetic risk for BRCA-related breast or ovarian cancer in women: recommendations from the U.S. Preventive Services Task Force.
    No paper-specific finding is recorded.
    PMID 24366402 ↗
  • Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.
    No paper-specific finding is recorded.
    PMID 27854360 ↗

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

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.045 Open source ↗
ClinVar 2 Uncertain significance Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 826675)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.659. BayesDel score = 0.247749.

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.