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BRCA1c.3800T>CBenign
Print report
Variant interpretation report

BRCA1 c.3800T>C, p.(Leu1267Ser)

NM_007294.4:c.3800T>C NP_009225.1:p.(Leu1267Ser) Missense · exon 10 View identifiers
Classification
Benign

Variant description:

No variant summary was recorded for this case.

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

Benign.A benign classification under the recorded framework.

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: 3
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 3
BS3Strong
BS3 · strong

Met, Strong: ENIGMA Table 9 pre-assigns BS3 Strong because calibrated testing found protein function similar to benign controls.

BP1Strong
BP1 · strong

Met, strong: residue 1267 is outside approved domains and SpliceAI max delta 0.034 is below the ENIGMA BP1 threshold of 0.1.

BP5Supporting
BP5 · supporting

Met, supporting: clinical-history LR 0.2734782711138511 <= 0.48? yes, and >0.23, matching the ENIGMA BP5 supporting range.

Recorded classification: Benign

Benign: BS3 (strong) plus BP1 (strong) satisfy ENIGMA's two-strong-benign rule, with BP5 (supporting) providing 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
9 / 1,614,102 alleles

gnomAD v4.1: 9 / 1,614,102 alleles. Recorded AF 5.57586e-06. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

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

Recorded REVEL score: 0.513. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied
ClinVar submissions
10 reported laboratory submissions

5 Uncertain significance · 4 Likely benign · 1 Uncertain Significance. ClinVar API review status: criteria provided, conflicting classifications.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Neutral; curated oncogenicity label: Likely Neutral.

Applied · BS3 → 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: 3 met · 10 not met · 5 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

For this missense variant, ENIGMA consequence rules make PVS1, PM4, and BP3 not applicable; none of these criteria is assigned.

For the requested codon, residue, and domain criteria, ENIGMA BRCA1 v1.2 yields BP1_Strong only; PS1 is not met because no pathogenic same-amino-acid comparator was found, while PM1, PM5, and PP2 are explicitly not used for this missense context.

The target variant is outside all governing BRCA1 clinically important or potentially clinically important domains, and its SpliceAI maximum delta is 0.034.

The variant is a BRCA1 missense substitution, c.3800T>C p.(Leu1267Ser), and the governing ENIGMA functional-assay table assigns BS3 Strong.

Functional evidence is concordantly neutral or non-impacting across the governing Table 9 record, supplementary functional dataset, and the explicitly variant-matched cisplatin complementation result; no PS3 damaging evidence is met.

Within this criterion group, BP5 Supporting is met from the exact BRCA1 c.3800T>C clinical-history LR of 0.2734782711138511; PP4 is not met because the same value is below the PP4 threshold.

PS4 is not assessed because no qualifying exact-variant case-control statistics were available, and PP5/BP6 are not met because ClinVar has no exact-variant expert-panel submission.

Met · 3

BS3 StrongMet, Strong: ENIGMA Table 9 pre-assigns BS3 Strong because calibrated testing found protein function similar to benign controls. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA1 Specifications Table 9 pre-assigns BS3 Strong for c.3800T>C p.(Leu1267Ser), stating that one calibrated study found protein function similar to benign control variants (PMID:32546644). The supplementary functional dataset independently records no functional impact and a neutral result. A separate calibrated cisplatin complementation assay also reports L1267S as neutral relative to the assay controls. This is protein functional evidence, matching the ENIGMA BS3 functional-assay rule.

Rule
ENIGMA BRCA1 V1.2 BS3 applies to well-established protein-only or combined mRNA/protein functional assays showing no damaging effect; Table 9 calibrated assignments govern.
Evidence considered
  • ENIGMA Specifications Table 9 explicitly pre-assigns BS3 Strong for BRCA1 c.3800T>C, p.(Leu1267Ser), based on a calibrated study reporting protein function similar to benign control variants (PMID:32546644).
  • ENIGMA supplementary functional data list c.3800T>C/p.(Leu1267Ser) as no functional impact, with a neutral outcome.
  • The ENIGMA specification defines BS3 functional evidence as well-established in vitro or in vivo evidence of no damaging effect measured through protein-only or combined mRNA/protein assays, with Table 9 as the calibrated source.
  • Bouwman et al. 2013 report L1267S c.3800T>C as neutral in a full-length BRCA1 cisplatin-response complementation assay using BRCA1-deficient mouse embryonic stem cells and wild-type and empty-vector controls.
Sources
vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18PMID:23867111 ↗PMID:32546644 ↗
BP1 StrongMet, strong: residue 1267 is outside approved domains and SpliceAI max delta 0.034 is below the ENIGMA BP1 threshold of 0.1. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 v1.2 BP1_Strong rule applies to missense variants outside a potentially clinically important functional domain when no splicing is predicted (SpliceAI <=0.1). The variant is a missense substitution at p.Leu1267Ser; residue 1267 is outside the governing BRCA1 RING aa 2-101, coiled-coil aa 1391-1424, and BRCT aa 1650-1857 domains. The case SpliceAI maximum delta is 0.034, which is below the <=0.1 threshold. The BRCA1 exon 11 coldspot analysis independently describes the region containing residue 1267 as a missense coldspot, with no confirmed pathogenic or likely pathogenic missense variants and an estimated pathogenicity odds ratio below 0.01.

Rule
ENIGMA BRCA1 v1.2 BP1_Strong: missense or qualifying in-frame variant outside a potentially clinically important functional domain and no predicted splicing (SpliceAI <=0.1).
Evidence considered
  • Specifications_V1.2_2024-11-18.docx defines BP1_Strong for missense variants outside a potentially clinically important functional domain with SpliceAI <=0.1.
  • The governing BRCA1 domains are RING aa 2-101, coiled-coil aa 1391-1424, and BRCT aa 1650-1857; p.Leu1267 is outside all listed domains.
  • Case evidence reports SpliceAI max delta 0.034, satisfying the ENIGMA BP1 <=0.1 requirement.
  • The exon 11 coldspot study reports that the region containing p.L1267 has no confirmed pathogenic or likely pathogenic missense variants and an estimated pathogenicity odds ratio below 0.01 (PMID:31911673).
Sources
cspec ↗PMID:31911673 ↗
BP5 SupportingMet, supporting: clinical-history LR 0.2734782711138511 <= 0.48? yes, and >0.23, matching the ENIGMA BP5 supporting range. Details ▾Hide ▴
Reasoning

ENIGMA restricts BP5 to clinically calibrated multifactorial likelihood evidence and specifies supporting BP5 as LR <=0.48 to >0.23. The exact BRCA1 c.3800T>C clinical-history row in Li et al. gives LR 0.2734782711138511. The criterion's operator is <=, and the explicit comparison is 0.2734782711138511 <= 0.48? yes; it is also >0.23, so BP5 Supporting is met. This source is used only as the clinical-history LR component permitted by the VCEP framework.

Rule
BP5 supporting: LR <=0.48 to >0.23:1; combined LR >0.48 and <1.00 is not informative for BP5.
Evidence considered
  • ENIGMA BP5 supporting rule: LR <=0.48 to >0.23:1; the criterion's operator is <=.
  • The exact Gene=BRCA1, HGVS_Nucleotide=c.3800T>C row reports LOG(LR) -1.296533107757568 and LR 0.2734782711138511 for 3 probands.
  • Explicit comparisons: 0.2734782711138511 <= 0.48? yes; 0.2734782711138511 > 0.23? yes.
Sources
cspec ↗vcep_pmid_31853058_brca1_clinical_history_lrPMID:31853058 ↗

Not met · 10 · evaluated, threshold not reached

PS1 Not met: SpliceAI max delta 0.034 qualifies, but no pathogenic or likely pathogenic alternate substitution at Leu1267 was found in the governing VCEP files. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 v1.2 specification permits PS1 for a missense substitution matching a previously established pathogenic variant at the amino-acid level, with no predicted splicing effect (SpliceAI <=0.1), and requires the reference variant to be classified using VCEP specifications. The governing VCEP files were searched for c.3800T>C, p.Leu1267Ser, and p.L1267S; they contain the target variant as neutral/likely benign functional or multifactorial evidence, but no different pathogenic or likely pathogenic missense substitution at Leu1267. The target variant's SpliceAI maximum delta is 0.034, satisfying the splice prerequisite, but the required pathogenic same-amino-acid comparator is not present.

Rule
ENIGMA BRCA1 v1.2 PS1: same missense amino-acid substitution as a previously established pathogenic or likely pathogenic variant; for protein-change application, no confirmed or predicted splicing effect (SpliceAI <=0.1).
Evidence considered
  • Specifications_V1.2_2024-11-18.docx states that PS1 may be applied for the same amino-acid change as a previously established pathogenic or likely pathogenic variant, with no confirmed or predicted mRNA-splicing effect; the VCEP files were searched under c.3800T>C, p.Leu1267Ser, and p.L1267S.
  • The exact target variant is reported by Bouwman et al. as L1267S c.3800T>C, VUS, neutral in a cisplatin-response complementation assay, so this record is not a pathogenic PS1 comparator (PMID:23867111).
  • The BRCA1 exon 11 coldspot analysis reports no confirmed pathogenic or likely pathogenic missense variants in the exon 11 region containing residue 1267 and an estimated pathogenicity odds ratio below 0.01 (PMID:31911673).
  • Case evidence reports SpliceAI max delta 0.034, below the ENIGMA PS1 missense prerequisite of 0.1.
Sources
cspec ↗PMID:23867111 ↗PMID:31911673 ↗
PS3 Not met: ENIGMA Table 9 reports protein function similar to benign controls and assigns BS3 Strong, not PS3, for c.3800T>C. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA1 Table 9 assigns no PS3 evidence to BRCA1 c.3800T>C p.(Leu1267Ser): the calibrated functional study reported protein function similar to benign controls, and the supplementary functional dataset records no functional impact. The cited cisplatin complementation assay classified L1267S as neutral, not damaging. Therefore, validated functional evidence does not support a damaging-effect code.

Rule
ENIGMA BRCA1 V1.2 PS3 applies to well-established protein-only or combined mRNA/protein assays supportive of a damaging effect; Table 9 calibrated assignments govern.
Evidence considered
  • ENIGMA Specifications Table 9 explicitly lists BRCA1 c.3800T>C, p.(Leu1267Ser), as BS3 Strong: one calibrated study reported protein function similar to benign control variants (PMID:32546644).
  • ENIGMA supplementary functional data list c.3800T>C/p.(Leu1267Ser) as having no functional impact, with two observations and a neutral outcome.
  • The ENIGMA specification requires PS3 functional assays to show a damaging effect and directs use of Table 9 calibrated assay assignments.
  • Bouwman et al. 2013 explicitly report L1267S c.3800T>C as a VUS with a neutral cisplatin-response functional classification in a BRCA1-deficient mouse embryonic stem-cell complementation assay.
Sources
vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18PMID:23867111 ↗PMID:32546644 ↗
PM2 Not met: gnomAD v3.1 non-cancer contains 1 allele (AF 6.75794e-06), violating the VCEP requirement for absence from both required datasets. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP assigns PM2_Supporting only when the variant is absent from both specified controls datasets: gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, with average regional read depth at least 25. The variant is absent from gnomAD v2.1 non-cancer but present in gnomAD v3.1 non-cancer at AF 6.75794e-06 (1/147974 alleles), so the bilateral absence requirement is not satisfied. The governing VCEP table also records the variant as absent in its historical frequency field, but the current required non-cancer dataset contains one allele; the direct dataset observation controls this criterion.

Rule
ENIGMA BRCA1 VCEP PM2_Supporting: variant must be absent from both gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, with average regional read depth >=25; otherwise do not apply PM2.
Evidence considered
  • ENIGMA BRCA1 VCEP v1.2 specifies PM2_Supporting for absence from gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, with average regional read depth >=25.
  • The case evidence reports gnomAD v2.1 non-cancer absent but gnomAD v3.1 non-cancer present at 1/147974 alleles, AF 6.75794e-06, with zero homozygotes.
  • The governing ENIGMA supplementary and multifactorial tables contain the exact variant row c.3800T>C / p.(Leu1267Ser) and label its historical frequency category as Absent; this does not override the current gnomAD v3.1 non-cancer observation for the VCEP bilateral-absence rule.
Sources
cspec ↗gnomad_v4 ↗vcep_supplementarytables_v1_2_2024_11_18vcep_humu_40_1557_s001
PP3 Not met: missense REVEL score 0.513 is below the 0.644 supporting PP3 threshold, and p.Leu1267Ser lies outside ENIGMA BRCA1 functional domains. Details ▾Hide ▴
Reasoning

NM_007294.4:c.3800T>C is a missense variant, p.Leu1267Ser. Under the ENIGMA BRCA1 VCEP specification, protein-impact PP3 is restricted to missense variants inside a potentially clinically important functional domain and requires a deleterious calibrated missense prediction; p.Leu1267 is outside the defined RING (aa 2-101), coiled-coil (aa 1391-1424), and BRCT (aa 1650-1857) domains. Following the required missense path, the available REVEL score is 0.513, below the generic ClinGen SVI supporting PP3 threshold of 0.644 (Pejaver et al. 2022, PMID:36413997), so PP3 is not met. The SpliceAI result is not used for missense PP3/BP4 adjudication.

Rule
ENIGMA BRCA1 VCEP v1.2 domain-specific PP3 rule; generic REVEL calibration used only because no variant-specific PP3 assignment was found.
Evidence considered
  • The ENIGMA BRCA1 VCEP defines clinically important domains as RING aa 2-101, coiled-coil aa 1391-1424, and BRCT aa 1650-1857; p.Leu1267Ser is outside these domains.
  • The case-specific missense predictor result is REVEL 0.513. The published generic ClinGen SVI REVEL supporting PP3 threshold is >=0.644, from Pejaver et al. 2022 (PMID:36413997).
  • The ENIGMA supplementary search found c.3800T>C / p.(Leu1267Ser) rows, but they are functional/reference-data rows and do not pre-assign PP3.
Still missing
  • No variant-specific PP3 code pre-assignment was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt; the c.3800T>C row is present as a functional/reference entry, not a PP3 assignment.
  • No variant-specific PP3 row was found in Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗revelvcep_appendices_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18
PP4 Not met: clinical-history LR 0.2734782711138511 >= 2.08? no, so it does not meet the ENIGMA PP4 supporting threshold. Details ▾Hide ▴
Reasoning

ENIGMA restricts PP4 to clinically calibrated multifactorial likelihood evidence and requires LR >=2.08 for supporting evidence. The exact BRCA1 c.3800T>C clinical-history row in Li et al. gives LR 0.2734782711138511. The required comparison is 0.2734782711138511 >= 2.08? no; therefore PP4 is not met. This value instead falls in the benign-supporting BP5 range.

Rule
PP4 supporting: LR >=2.08:1; combined LR >0.48 and <2.08 is not informative for PP4/BP5.
Evidence considered
  • ENIGMA PP4 supporting rule: LR >=2.08:1; the criterion's operator is >=.
  • The exact Gene=BRCA1, HGVS_Nucleotide=c.3800T>C row reports LOG(LR) -1.296533107757568 and LR 0.2734782711138511 for 3 probands.
  • Explicit comparison: 0.2734782711138511 >= 2.08? no.
Sources
cspec ↗vcep_pmid_31853058_brca1_clinical_history_lrPMID:31853058 ↗
PP5 Not met: exact-match ClinVar record 142031 has 0 expert-panel submissions and no Pathogenic or Likely pathogenic expert-panel classification. Details ▾Hide ▴
Reasoning

PP5 is restricted here to an exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic. ClinVar variation 142031 exactly matches NM_007294.4:c.3800T>C (p.Leu1267Ser), but the record reports no expert-panel submissions and only single-submitter laboratory classifications of uncertain significance or likely benign. Therefore the required expert-panel pathogenic/likely-pathogenic assertion is not present.

Rule
Apply only for an exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic; ordinary laboratory submissions and aggregate labels do not qualify.
Evidence considered
  • The exact-match ClinVar record is NM_007294.4(BRCA1):c.3800T>C (p.Leu1267Ser), variation 142031.
  • ClinVar reports expert_panels as an empty object and summarizes only single-clinical-laboratory classifications: uncertain significance and likely benign.
  • PP5 was evaluated only under the requested rule requiring an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification.
Sources
clinvar ↗cspec ↗
BA1 Not met: maximum gnomAD filter allele frequency is 3.59e-06, far below the ENIGMA BA1 threshold of >0.001. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP assigns BA1 when the maximum filter allele frequency exceeds 0.001 (0.1%) in the specified non-cancer, non-founder gnomAD populations. The maximum available gnomAD v4.1 grpmax FAF is 3.59e-06, and the required older non-cancer datasets do not approach the BA1 threshold: gnomAD v2.1 non-cancer is absent and gnomAD v3.1 non-cancer has AF 6.75794e-06. Therefore BA1 is not met.

Rule
ENIGMA BRCA1 VCEP BA1: apply when FAF >0.001 in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer non-founder populations; exclude failed-QC data and require read depth >=20.
Evidence considered
  • ENIGMA BRCA1 VCEP v1.2 specifies BA1 for filter allele frequency above 0.001 in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer populations.
  • gnomAD v4.1 reports grpmax FAF 3.59e-06, total AF 5.575855800934514e-06, and European non-Finnish AF 7.62687303290233e-06, all below 0.001.
  • The required non-cancer datasets report gnomAD v2.1 non-cancer absent and gnomAD v3.1 non-cancer AF 6.75794e-06, with zero homozygotes.
Sources
cspec ↗gnomad_v4 ↗
BS1 Not met: maximum gnomAD filter allele frequency is 3.59e-06, below the ENIGMA BS1_Supporting lower threshold of >0.00002. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP assigns BS1 when the maximum filter allele frequency exceeds 0.0001, or BS1_Supporting when it is above 0.00002 and at most 0.0001, in the specified non-cancer, non-founder gnomAD populations. The maximum available gnomAD v4.1 grpmax FAF is 3.59e-06, and gnomAD v3.1 non-cancer reports AF 6.75794e-06 with grpmax FAF 0; these are below even the BS1_Supporting threshold. Therefore BS1 is not met.

Rule
ENIGMA BRCA1 VCEP BS1: apply BS1 at FAF >0.0001 and BS1_Supporting at FAF >0.00002 to <=0.0001 in specified non-cancer, non-founder gnomAD populations; require read depth >=20.
Evidence considered
  • ENIGMA BRCA1 VCEP v1.2 specifies BS1 for FAF >0.0001 and BS1_Supporting for FAF >0.00002 to <=0.0001 in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer populations.
  • gnomAD v4.1 reports grpmax FAF 3.59e-06; the highest observed non-Finnish European AF is 7.62687303290233e-06.
  • gnomAD v3.1 non-cancer reports AF 6.75794e-06 and grpmax FAF 0, both below the VCEP BS1_Supporting threshold.
Sources
cspec ↗gnomad_v4 ↗
BP4 Not met: missense REVEL score 0.513 exceeds the 0.29 supporting BP4 threshold and is indeterminate, with p.Leu1267Ser outside ENIGMA BRCA1 domains. Details ▾Hide ▴
Reasoning

NM_007294.4:c.3800T>C is a missense variant, p.Leu1267Ser. Under the ENIGMA BRCA1 VCEP specification, missense BP4 is defined for variants inside a potentially clinically important functional domain with no predicted protein or splice impact; p.Leu1267 is outside the defined BRCA1 functional domains. Independently, on the required missense REVEL path, the score is 0.513, above the generic ClinGen SVI supporting BP4 threshold of 0.29 (Pejaver et al. 2022, PMID:36413997), placing it in the indeterminate interval rather than supporting benign evidence. The SpliceAI result is not substituted for or used as missense BP4 evidence.

Rule
ENIGMA BRCA1 VCEP v1.2 domain-specific BP4 rule; generic REVEL calibration used only because no variant-specific BP4 assignment was found.
Evidence considered
  • The ENIGMA BRCA1 VCEP restricts missense BP4 to variants inside a potentially clinically important functional domain; p.Leu1267Ser is outside the RING, coiled-coil, and BRCT domains defined by the VCEP.
  • The case-specific missense predictor result is REVEL 0.513. The published generic ClinGen SVI REVEL supporting BP4 threshold is <=0.29, from Pejaver et al. 2022 (PMID:36413997); 0.513 is therefore indeterminate for BP4.
  • The ENIGMA supplementary search found c.3800T>C / p.(Leu1267Ser) rows, but they do not pre-assign BP4.
Still missing
  • No variant-specific BP4 code pre-assignment was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt; the c.3800T>C row is present as a functional/reference entry, not a BP4 assignment.
  • No variant-specific BP4 row was found in Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗revelvcep_appendices_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18
BP6 Not met: exact-match ClinVar record 142031 has 0 expert-panel submissions, so laboratory Likely benign assertions cannot trigger BP6. Details ▾Hide ▴
Reasoning

BP6 is restricted here to an exact-variant ClinVar expert-panel classification of Benign or Likely benign. ClinVar variation 142031 exactly matches NM_007294.4:c.3800T>C (p.Leu1267Ser), but the record reports no expert-panel submissions; its likely-benign assertions are from individual laboratories and do not qualify. Therefore the required expert-panel benign/likely-benign assertion is not present.

Rule
Apply only for an exact-variant ClinVar expert-panel classification of Benign or Likely benign; ordinary laboratory submissions and aggregate labels do not qualify.
Evidence considered
  • The exact-match ClinVar record is NM_007294.4(BRCA1):c.3800T>C (p.Leu1267Ser), variation 142031.
  • ClinVar reports expert_panels as an empty object; likely-benign classifications are single-submitter laboratory assertions.
  • BP6 was evaluated only under the requested rule requiring an exact-variant ClinVar expert-panel Benign or Likely benign classification.
Sources
clinvar ↗cspec ↗

Not assessed · 5 · no assessment recorded

PS4 Not assessed: no exact-variant case-control p-value, odds ratio, or confidence interval was available to test the PS4 requirements. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 specification requires case-control evidence with p-value <=0.05, odds ratio >=4, and a lower confidence interval excluding 2.0. The exact-variant searches found no PS4 case-control entry in Specifications_V1.2_2024-11-18.docx.txt, and the supplied case evidence contains no qualifying exact-variant case-control p-value, odds ratio, or confidence interval. The Li et al. clinical-history LR file is explicitly restricted to PP4/BP5 and cannot be used for PS4.

Rule
Case-control studies; p-value <=0.05 and OR >=4 (lower confidence interval excludes 2.0).
Evidence considered
  • ENIGMA specifies PS4 as case-control studies with p-value <=0.05 and OR >=4, with the lower confidence interval excluding 2.0.
  • The exact-variant searches for c.3800T>C, p.Leu1267Ser, and p.L1267S found no PS4 row in Specifications_V1.2_2024-11-18.docx.txt.
  • The Li et al. clinical-history source states that its data are for PP4/BP5 only and must not be used for PS4.
Still missing
  • No exact-variant PS4 case-control entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • A qualifying case-control p-value, odds ratio, and lower confidence interval were not available in the case evidence.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PM3 Not assessed: ENIGMA PM3 requires Fanconi-anemia phenotype plus same-gene pathogenic co-occurrence; no affected-proband, phase, or Fanconi-anemia evidence is documented. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA1 VCEP specification restricts PM3 to a patient with a phenotype consistent with BRCA1-related Fanconi anemia and a co-occurring pathogenic or likely pathogenic variant in the same gene. PM3 points are assigned only from qualifying affected probands: 2 points for a P/LP variant in trans or homozygous with the assessment variant, or 1 point when phase is unknown; PM3 is assigned at 1 point, 2 points, or at least 4 points for supporting, moderate, or strong evidence, respectively. The reviewed case evidence documents no Fanconi-anemia phenotype, affected-proband observation, pathogenic same-gene partner, phase, or homozygosity for NM_007294.4:c.3800T>C (p.Leu1267Ser). Therefore, PM3 cannot be assigned from the available evidence.

Rule
ENIGMA BRCA1 VCEP PM3_VariableWeight: apply only for a patient with phenotype consistent with BRCA1-related Fanconi anemia and co-occurring variants in the same gene; PM3_Supporting = 1 point, PM3 = 2 points, PM3_Strong = 4 or more points.
Evidence considered
  • ENIGMA BRCA1/2 Specifications v1.2, Table 1 and Table 6: PM3 is restricted to BRCA1-related Fanconi-anemia phenotype with a same-gene pathogenic/likely pathogenic co-occurring variant; 1 point is supporting, 2 points is moderate, and at least 4 points is strong.
  • The case evidence bundle and vcep_materials.json contain no documented affected Fanconi-anemia proband, same-gene pathogenic partner, phase, in-trans observation, or homozygosity for NM_007294.4:c.3800T>C (p.Leu1267Ser).
  • The exact variant was searched in the governing BRCA1 VCEP full-text files under c.3800T>C, p.Leu1267Ser, and p.L1267S; the located entries concern functional or multifactorial data, not PM3 allelic observations.
Still missing
  • No qualifying Fanconi-anemia phenotype or affected-proband record was found in the case_evidence_bundle_allelic.txt bundle or output/vcep_materials.json.
  • No pathogenic/likely pathogenic BRCA1 co-occurring variant, phase determination, in-trans observation, or homozygous observation was found in the case_evidence_bundle_allelic.txt bundle or output/vcep_materials.json.
  • Specifications_V1.2_2024-11-18.docx.txt was searched for the governing PM3 rule and variant notations; it contains the PM3 framework and Table 6 thresholds but no case-specific PM3 observation for c.3800T>C, p.Leu1267Ser, or p.L1267S.
Sources
cspec ↗
PP1 Not assessed: the exact variant row has no segregation LR, while the available clinical-history LR is 0.2734782711138511 and is not a co-segregation measure. Details ▾Hide ▴
Reasoning

The ENIGMA specification requires quantitative co-segregation analysis and assigns PP1 strength at LR >=2.08, PP1_Moderate at LR >=4.3, PP1_Strong at LR >=18.7, and PP1_Very Strong at LR >=350. The exact c.3800T>C/p.(Leu1267Ser)/L1267S row in HUMU-40-1557-s001 has a blank Segregation LR. The available exact-variant clinical-history LR is 0.2734782711138511 from 3 probands, but that source is a clinical-history component and is not a co-segregation LR; therefore it cannot establish PP1.

Rule
ENIGMA BRCA1/2 VCEP v1.2 PP1: quantitative co-segregation required; PP1 >=2.08:1, PP1_Moderate >=4.3:1, PP1_Strong >=18.7:1, PP1_Very Strong >=350:1.
Evidence considered
  • Specifications_V1.2_2024-11-18.docx Table 1 requires quantitative co-segregation analysis and sets PP1 thresholds at LR >=2.08, PP1_Moderate >=4.3, PP1_Strong >=18.7, and PP1_Very Strong >=350.
  • HUMU-40-1557-s001.xlsx exact row BRCA1 c.3800T>C, p.(Leu1267Ser), L1267S reports no Segregation LR; its combined LR is 0.21 and its clinical components include pathology LR 0.21, not a segregation result.
  • The exact variant row in the Li et al. clinical-history dataset reports LOG(LR) -1.296533107757568, LR 0.2734782711138511, and N_Probands 3; this is a clinical-history LR component and the VCEP guidance says it must not be used alone for PP1 or segregation.
  • Parsons et al. 2019 describes the multifactorial framework, but its extracted finding states that BRCA1 c.3800T>C/p.(L1267S) is not explicitly mentioned and no variant-specific segregation result is provided.
Still missing
  • No variant-specific quantitative co-segregation LR, affected-relative genotype data, meioses, or family pedigree was found for c.3800T>C/p.(Leu1267Ser)/L1267S in HUMU-40-1557-s001; its Segregation LR field is blank.
  • No variant-specific PP1 entry was found in Specifications_V1.2_2024-11-18.docx.
Sources
cspec ↗vcep_humu_40_1557_s001vcep_pmid_31853058_brca1_clinical_history_lrPMID:31131967 ↗PMID:31853058 ↗
BS2 Not assessed: gnomAD shows 0 homozygotes, and no qualifying phenotyped healthy individual or phase-specific cohort observation is available. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP BS2 rule requires variant observations in phenotyped clinical or research-cohort individuals who are homozygous, or in trans with a pathogenic or likely pathogenic allele, and who lack the relevant Fanconi Anemia phenotype; point totals determine strength. The available gnomAD data show zero homozygotes, and the VCEP explicitly states that gnomAD homozygote observations are not used for BS2. No qualifying phenotyped individual or phase-specific clinical observation is available in the reviewed case evidence.

Rule
ENIGMA BRCA1 VCEP BS2: assess only phenotyped clinical or research-cohort individuals who are homozygous, in trans with a P/LP allele, or phase-unknown with a P/LP allele and lack Fanconi Anemia features; assign strength from accumulated points.
Evidence considered
  • ENIGMA BRCA1 VCEP BS2 requires phenotyped individuals without Fanconi Anemia features and uses point totals: BS2 at >=4 points, BS2_Moderate at 2 points, and BS2_Supporting at 1 point.
  • The VCEP Appendix H states that BS2 applies to clinical or research-cohort individuals and is not applied to frequency-based gnomAD observations; gnomAD homozygotes are already captured by BA1 or BS1 when applicable.
  • gnomAD v4.1 reports total homozygotes 0, and gnomAD v3.1 non-cancer reports homozygotes 0.
Still missing
  • No qualifying phenotyped clinical or research-cohort observation documenting homozygosity or trans phase with a pathogenic/likely pathogenic BRCA1 allele and absence of Fanconi Anemia features.
Sources
cspec ↗gnomad_v4 ↗
BS4 Not assessed: the exact variant row has no segregation LR, and the available clinical-history LR 0.2734782711138511 is not evidence of non-segregation. Details ▾Hide ▴
Reasoning

The ENIGMA specification requires quantitative evidence of lack of segregation and assigns BS4_Supporting at LR <=0.48, BS4_Moderate at LR <=0.23, BS4 at LR <=0.05, and BS4_Very Strong at LR <=0.00285. The exact c.3800T>C/p.(Leu1267Ser)/L1267S row in HUMU-40-1557-s001 has a blank Segregation LR. The available exact-variant clinical-history LR is 0.2734782711138511 from 3 probands, but it is not a segregation LR and cannot establish BS4.

Rule
ENIGMA BRCA1/2 VCEP v1.2 BS4: quantitative lack of segregation required; BS4_Supporting <=0.48:1, BS4_Moderate <=0.23:1, BS4 <=0.05:1, BS4_Very Strong <=0.00285:1.
Evidence considered
  • Specifications_V1.2_2024-11-18.docx Table 1 requires quantitative co-segregation analysis for BS4 and sets BS4_Supporting at LR <=0.48, BS4_Moderate at LR <=0.23, BS4 at LR <=0.05, and BS4_Very Strong at LR <=0.00285.
  • HUMU-40-1557-s001.xlsx exact row BRCA1 c.3800T>C, p.(Leu1267Ser), L1267S reports no Segregation LR; therefore it provides no quantitative non-segregation evidence for BS4.
  • The exact variant row in the Li et al. clinical-history dataset reports LR 0.2734782711138511 from 3 probands; this is a clinical-history LR component and the VCEP guidance says it must not be used alone for BS4 or segregation.
  • Parsons et al. 2019 describes the multifactorial framework, but its extracted finding states that BRCA1 c.3800T>C/p.(L1267S) is not explicitly mentioned and no variant-specific segregation result is provided.
Still missing
  • No variant-specific quantitative non-segregation LR, affected-relative genotype data, meioses, or family pedigree was found for c.3800T>C/p.(Leu1267Ser)/L1267S in HUMU-40-1557-s001; its Segregation LR field is blank.
  • No variant-specific BS4 entry was found in Specifications_V1.2_2024-11-18.docx.
Sources
cspec ↗vcep_humu_40_1557_s001vcep_pmid_31853058_brca1_clinical_history_lrPMID:31131967 ↗PMID:31853058 ↗
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: c.3800T>C is a missense substitution, whereas ENIGMA PVS1 is restricted to qualifying loss-of-function null variants. Details ▾Hide ▴
Reasoning

The variant is NM_007294.4:c.3800T>C, p.(Leu1267Ser), a missense substitution. The ENIGMA BRCA1/2 specification applies PVS1 to null variants such as nonsense, frameshift, canonical +/-1,2 splice-site, initiation-codon, or exon-deletion variants in a gene where loss of function is a disease mechanism; this missense variant does not meet those consequence requirements. The governing Specifications_Table4_V1.2_2024-11-18.xlsx was searched under c.3800T>C, p.Leu1267Ser, and p.L1267S with no exact variant entry, and the specification's PVS1 framework was reviewed. Therefore PVS1 is not applicable, rather than a downgraded PVS1 call.

Rule
ENIGMA BRCA1/2 Specification v1.2 PVS1 rule: null variants only; missense substitutions are not applicable.
Evidence considered
  • The case normalization identifies NM_007294.4:c.3800T>C as NP_009225.1:p.(Leu1267Ser), p.(L1267S), with consequence class missense.
  • ENIGMA BRCA1/2 Specification v1.2 lists PVS1 for qualifying null variants and directs strength assignment through its PVS1 flowchart; a missense substitution is outside that applicability statement.
  • Specifications_Table4_V1.2_2024-11-18.xlsx was searched for c.3800T>C, p.Leu1267Ser, and p.L1267S; no exact variant row was found.
Still missing
  • No exact c.3800T>C, p.Leu1267Ser, or p.L1267S entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx; this does not alter the missense-based non-applicability determination.
  • No exact c.3800T>C, p.Leu1267Ser, or p.L1267S entry was found in Specifications_V1.2_2024-11-18.docx; this does not alter the missense-based non-applicability determination.
  • No exact c.3800T>C, p.Leu1267Ser, or p.L1267S entry was found in Appendices_V1.2_2024-11-18.docx; this does not alter the missense-based non-applicability determination.
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18
PS2 VCEPNot applicable: ENIGMA prohibits PS2 because de novo occurrences lack calibrated predictive capacity for commonly occurring BRCA1/2-related cancers. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 VCEP specification explicitly states that PS2 is not to be used because BRCA1/2-related cancers occur relatively commonly and the predictive capacity of de novo occurrences has not been calibrated.

VCEP rule
ENIGMA BRCA1/2 VCEP v1.2: PS2 do not use; no calibrated predictive capacity for de novo occurrences in BRCA1/2-related cancers.
Evidence considered
  • Specifications_V1.2_2024-11-18.docx Table 1 states for PS2: "Do not use" because BRCA1/2-related cancers occur relatively commonly and there is no information to calibrate the predictive capacity of de novo occurrences.
  • The case evidence contains no variant-specific de novo observation that could override the governing VCEP prohibition.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PM1 VCEPNot applicable: ENIGMA does not use PM1, and residue 1267 lies outside BRCA1 RING 2-101, coiled-coil 1391-1424, and BRCT 1650-1857 domains. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA1 v1.2 specification explicitly states that PM1 is not used and is considered as a component of the bioinformatic analysis under PP3/BP4. The variant is p.Leu1267Ser, and the VCEP functional-domain list places BRCA1 critical or potentially critical domains at RING aa 2-101, coiled-coil aa 1391-1424, and BRCT aa 1650-1857; residue 1267 is outside all three. vcep_materials.json has no gene-specific domain_tables entry, so the governing specification's complete domain list was used.

VCEP rule
ENIGMA BRCA1 v1.2 PM1: do not use; treat domain/hotspot information as part of PP3/BP4 instead.
Evidence considered
  • Specifications_V1.2_2024-11-18.docx explicitly marks PM1 as do not use and states that it is considered as a component of PP3/BP4 bioinformatic analysis.
  • The governing BRCA1 domain definitions are RING aa 2-101, coiled-coil aa 1391-1424, and BRCT aa 1650-1857; residue 1267 is outside every listed domain.
  • vcep_materials.json was checked and its domain_tables key is empty; therefore the complete domain list in the governing VCEP specification was applied.
Sources
cspec ↗
PM4 VCEPNot applicable: p.(Leu1267Ser) changes one amino acid without the in-frame insertion, deletion, or stop-loss protein-length change required for PM4. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 Specification v1.2 defines PM4 as protein-length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants, and explicitly marks PM4 as Do not use for this framework. c.3800T>C produces the missense change p.(Leu1267Ser), with no insertion, deletion, delins, stop-loss event, or protein-length change. The governing Specifications_V1.2_2024-11-18.docx, Appendices_V1.2_2024-11-18.docx, and Specifications_Table4_V1.2_2024-11-18.xlsx were searched under c.3800T>C, p.Leu1267Ser, and p.L1267S; no exact variant entry was found. PM4 is therefore not applicable.

VCEP rule
ENIGMA BRCA1/2 Specification v1.2 PM4 rule: Do not use; defined protein-length-change events do not apply to this missense variant.
Evidence considered
  • The case normalization identifies p.(Leu1267Ser), a missense substitution with no protein-length change.
  • ENIGMA Specification v1.2 defines PM4 for in-frame insertion/deletion length changes in non-repeat regions or stop-loss variants and marks the criterion Do not use.
  • The governing VCEP files were searched for c.3800T>C, p.Leu1267Ser, and p.L1267S; no exact variant row was found.
Still missing
  • No exact c.3800T>C, p.Leu1267Ser, or p.L1267S entry was found in Specifications_V1.2_2024-11-18.docx; the specification nevertheless explicitly marks PM4 Do not use.
  • No exact c.3800T>C, p.Leu1267Ser, or p.L1267S entry was found in Appendices_V1.2_2024-11-18.docx.
  • No exact c.3800T>C, p.Leu1267Ser, or p.L1267S entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_specifications_table4_v1_2_2024_11_18
PM5 N/ANot applicable: ENIGMA excludes classic missense PM5, while its repurposed PM5 rule applies only to protein-termination-codon variants. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA1 v1.2 specification explicitly does not use classic missense PM5 and states that it is considered as a component of PP3/BP4. Its repurposed PM5_VariableWeight applies only to protein-termination-codon variants in an exon with a different proven pathogenic PTC variant and is not applicable to this missense variant. The target is NM_007294.4:c.3800T>C, p.(Leu1267Ser), not a PTC.

Rule
ENIGMA BRCA1 v1.2 PM5: classic missense PM5 do not use; PM5_VariableWeight is restricted to genomic PTC variants with PVS1.
Evidence considered
  • Specifications_V1.2_2024-11-18.docx states that classic missense PM5 is do not use and is considered as a component of PP3/BP4.
  • The same specification restricts repurposed PM5_VariableWeight to genomic protein-termination-codon variants annotated with PVS1; this case is a missense substitution.
Sources
cspec ↗
PM6 VCEPNot applicable: ENIGMA prohibits PM6 because de novo occurrences lack calibrated predictive capacity for commonly occurring BRCA1/2-related cancers. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 VCEP specification explicitly states that PM6 is not to be used for the same reason as PS2: BRCA1/2-related cancers occur relatively commonly and the predictive capacity of de novo occurrences has not been calibrated.

VCEP rule
ENIGMA BRCA1/2 VCEP v1.2: PM6 do not use; no calibrated predictive capacity for de novo occurrences in BRCA1/2-related cancers.
Evidence considered
  • Specifications_V1.2_2024-11-18.docx Table 1 states for PM6: "Do not use" because BRCA1/2-related cancers occur relatively commonly and there is no information to calibrate the predictive capacity of de novo occurrences.
  • The case evidence contains no variant-specific de novo observation that could override the governing VCEP prohibition.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PP2 VCEPNot applicable: ENIGMA marks PP2 as do not use because BRCA1 has a high frequency of benign missense variants. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA1 v1.2 specification explicitly marks PP2 as do not use because of a high frequency of benign missense variants. No PP2 evidence is assigned.

VCEP rule
ENIGMA BRCA1 v1.2 PP2: do not use; high frequency of benign missense variants.
Evidence considered
  • Specifications_V1.2_2024-11-18.docx marks PP2 as do not use and gives high frequency of benign missense variants as the reason.
Sources
cspec ↗
BP2 VCEPNot applicable: ENIGMA explicitly prohibits BP2 for BRCA1 and limits its use to the BS2 context. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA1 VCEP specification explicitly states that BP2 is not to be used and is applied only in the context of BS2. BP2 therefore is not applicable to this BRCA1 variant, regardless of whether any cis or trans co-occurrence observation is available.

VCEP rule
ENIGMA BRCA1 VCEP BP2: do not use; applied only in the context of BS2.
Evidence considered
  • ENIGMA BRCA1/2 Specifications v1.2, Table 1: BP2 is marked “Do not use” and is applied only in the context of BS2.
  • The exact variant notations c.3800T>C, p.Leu1267Ser, and p.L1267S were searched in the governing BRCA1 VCEP full-text files; no variant-specific BP2 assignment overrides the explicit VCEP prohibition.
Sources
cspec ↗
BP3 VCEPNot applicable: p.(Leu1267Ser) is a missense substitution, whereas ENIGMA BP3 is not used and concerns in-frame indels in nonfunctional repetitive regions. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 Specification v1.2 defines BP3 for in-frame deletions or insertions in a repetitive region without a known function, explicitly marks BP3 as Do not use, and states that the relevant assessment is captured by bioinformatic and domain analysis. c.3800T>C is a missense substitution, not an in-frame insertion or deletion, and there is no repeat-region length-changing event to assess. The governing Specifications_V1.2_2024-11-18.docx and Appendices_V1.2_2024-11-18.docx were searched under c.3800T>C, p.Leu1267Ser, and p.L1267S; no exact variant entry was found. BP3 is therefore not applicable.

VCEP rule
ENIGMA BRCA1/2 Specification v1.2 BP3 rule: Do not use; the defined repetitive-region in-frame-indel scenario is absent.
Evidence considered
  • The case normalization identifies p.(Leu1267Ser), a missense substitution rather than an in-frame insertion or deletion.
  • ENIGMA Specification v1.2 defines BP3 for in-frame indels in repetitive regions without known function, marks BP3 Do not use, and directs relevant assessment to bioinformatic and domain analysis.
  • The governing VCEP files were searched for c.3800T>C, p.Leu1267Ser, and p.L1267S; no exact variant row was found.
Still missing
  • No exact c.3800T>C, p.Leu1267Ser, or p.L1267S entry was found in Specifications_V1.2_2024-11-18.docx; the specification nevertheless explicitly marks BP3 Do not use.
  • No exact c.3800T>C, p.Leu1267Ser, or p.L1267S entry was found in Appendices_V1.2_2024-11-18.docx.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18
BP7 N/ANot applicable: c.3800T>C is a missense variant producing p.Leu1267Ser, whereas BP7 is restricted to synonymous or qualifying intronic variants. Details ▾Hide ▴
Reasoning

BP7 applies only to synonymous or qualifying intronic variants. NM_007294.4:c.3800T>C produces the missense substitution p.Leu1267Ser, so BP7 is out of scope and no splice or conservation predictor was evaluated for this criterion.

Rule
ENIGMA BRCA1 VCEP v1.2 BP7 scope rule.
Evidence considered
  • The normalized consequence is missense: NM_007294.4:c.3800T>C, NP_009225.1:p.(Leu1267Ser).
  • The ENIGMA BRCA1 VCEP defines BP7 for silent variants and qualifying intronic variants, not missense substitutions.
Sources
cspec ↗vcep_appendices_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18

Identifiers

Gene
BRCA1
Transcript
NM_007294.4
Coding (HGVS c.)
NM_007294.4:c.3800T>C
Protein (HGVS p.)
NP_009225.1:p.(Leu1267Ser)
GRCh38
chr17:43091731 A>G
GRCh37
chr17:41243748 A>G
Location and type
Exon 10 · missense
ClinVar
632684, 142031, 55262

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 9 / 1,614,102 alleles AF 5.58e-06 · 0 homozygotes · FAF 3.59e-06
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 5.6e-06 · 9 / 1,614,102 alleles · 0 hom · FAF 3.6e-06
European (non-Finnish)9 / 1,180,038 7.6e-06
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 5.57586e-06; MAF= 0.00056%, 9/1614102 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.62687e-06; MAF= 0.00076%, 9/1180038 alleles, homozygotes = 0); grpmax FAF= 3.59e-06.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -98 bp
0.018
SpliceAI acceptor gainat +79 bp
0.006
SpliceAI donor lossat +106 bp
0.011
SpliceAI donor gainat -19 bp
0.034
Pangolin splice lossmagnitude shown
-0.025
Pangolin splice gain
0.053

Other predictors

REVEL
0.513
BayesDel
-0.179

How the predictions were used

PP3 Not met: missense REVEL score 0.513 is below the 0.644 supporting PP3 threshold, and p.Leu1267Ser lies outside ENIGMA BRCA1 functional domains. Details ▾Hide ▴
Reasoning

NM_007294.4:c.3800T>C is a missense variant, p.Leu1267Ser. Under the ENIGMA BRCA1 VCEP specification, protein-impact PP3 is restricted to missense variants inside a potentially clinically important functional domain and requires a deleterious calibrated missense prediction; p.Leu1267 is outside the defined RING (aa 2-101), coiled-coil (aa 1391-1424), and BRCT (aa 1650-1857) domains. Following the required missense path, the available REVEL score is 0.513, below the generic ClinGen SVI supporting PP3 threshold of 0.644 (Pejaver et al. 2022, PMID:36413997), so PP3 is not met. The SpliceAI result is not used for missense PP3/BP4 adjudication.

Rule
ENIGMA BRCA1 VCEP v1.2 domain-specific PP3 rule; generic REVEL calibration used only because no variant-specific PP3 assignment was found.
Evidence considered
  • The ENIGMA BRCA1 VCEP defines clinically important domains as RING aa 2-101, coiled-coil aa 1391-1424, and BRCT aa 1650-1857; p.Leu1267Ser is outside these domains.
  • The case-specific missense predictor result is REVEL 0.513. The published generic ClinGen SVI REVEL supporting PP3 threshold is >=0.644, from Pejaver et al. 2022 (PMID:36413997).
  • The ENIGMA supplementary search found c.3800T>C / p.(Leu1267Ser) rows, but they are functional/reference-data rows and do not pre-assign PP3.
Still missing
  • No variant-specific PP3 code pre-assignment was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt; the c.3800T>C row is present as a functional/reference entry, not a PP3 assignment.
  • No variant-specific PP3 row was found in Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗revelvcep_appendices_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18
BP4 Not met: missense REVEL score 0.513 exceeds the 0.29 supporting BP4 threshold and is indeterminate, with p.Leu1267Ser outside ENIGMA BRCA1 domains. Details ▾Hide ▴
Reasoning

NM_007294.4:c.3800T>C is a missense variant, p.Leu1267Ser. Under the ENIGMA BRCA1 VCEP specification, missense BP4 is defined for variants inside a potentially clinically important functional domain with no predicted protein or splice impact; p.Leu1267 is outside the defined BRCA1 functional domains. Independently, on the required missense REVEL path, the score is 0.513, above the generic ClinGen SVI supporting BP4 threshold of 0.29 (Pejaver et al. 2022, PMID:36413997), placing it in the indeterminate interval rather than supporting benign evidence. The SpliceAI result is not substituted for or used as missense BP4 evidence.

Rule
ENIGMA BRCA1 VCEP v1.2 domain-specific BP4 rule; generic REVEL calibration used only because no variant-specific BP4 assignment was found.
Evidence considered
  • The ENIGMA BRCA1 VCEP restricts missense BP4 to variants inside a potentially clinically important functional domain; p.Leu1267Ser is outside the RING, coiled-coil, and BRCT domains defined by the VCEP.
  • The case-specific missense predictor result is REVEL 0.513. The published generic ClinGen SVI REVEL supporting BP4 threshold is <=0.29, from Pejaver et al. 2022 (PMID:36413997); 0.513 is therefore indeterminate for BP4.
  • The ENIGMA supplementary search found c.3800T>C / p.(Leu1267Ser) rows, but they do not pre-assign BP4.
Still missing
  • No variant-specific BP4 code pre-assignment was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt; the c.3800T>C row is present as a functional/reference entry, not a BP4 assignment.
  • No variant-specific BP4 row was found in Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗revelvcep_appendices_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18
BP7 N/ANot applicable: c.3800T>C is a missense variant producing p.Leu1267Ser, whereas BP7 is restricted to synonymous or qualifying intronic variants. Details ▾Hide ▴
Reasoning

BP7 applies only to synonymous or qualifying intronic variants. NM_007294.4:c.3800T>C produces the missense substitution p.Leu1267Ser, so BP7 is out of scope and no splice or conservation predictor was evaluated for this criterion.

Rule
ENIGMA BRCA1 VCEP v1.2 BP7 scope rule.
Evidence considered
  • The normalized consequence is missense: NM_007294.4:c.3800T>C, NP_009225.1:p.(Leu1267Ser).
  • The ENIGMA BRCA1 VCEP defines BP7 for silent variants and qualifying intronic variants, not missense substitutions.
Sources
cspec ↗vcep_appendices_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.513. BayesDel score = -0.178917.

8 paper records listed. 3 cited in the classification.

Cited in the classification

  • A high-throughput functional complementation assay for classification of BRCA1 missense variants.
    Bouwman P et al. · 2013 Oct
    Bouwman et al. explicitly report BRCA1 L1267S (c.3800T>C) as a VUS classified as neutral in a cisplatin-response functional complementation assay.
    → BS3 · strong Names this variant
    PMID 23867111 ↗
    Source detail
    L1267S c.3800T>C VUS Neutral

    Location Table 1, Functional classification of BRCA1 VUS based on cisplatin response

    Context Full-length human BRCA1 cDNA variants were tested in Brca1-deficient mouse embryonic stem cells using proliferation and cisplatin-sensitivity assays.

  • Li et al. 2020 BRCA1/2 clinical-history likelihood-ratio model
    The gene-specific clinical-history likelihood-ratio table contains an exact BRCA1 c.3800T>C row with LOG(LR) -1.296533107757568, 3 probands, and LR 0.2734782711138511. Under the ENIGMA thresholds, this supports BP5 at Supporting strength and does not support PP4.
    → BP5 · supporting Names this variant
    PMID 31853058 ↗
    Source detail
    BRCA1 c.3800T>C c.3800T>C -1.296533107757568 3 0.2734782711138511

    Location PMID_31853058_BRCA1_clinical_history_LR.xlsx, Sheet1, exact variant row

    Context Li et al. 2020 clinical-history logistic-regression model using personal and family-history data; the gene-specific table reports the variant-level LR component for 3 probands.

  • Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots".
    Dines JN et al. · 2020 May
    The study places p.L1267S within BRCA1 exon 11, a missense coldspot containing no confirmed pathogenic or likely pathogenic missense variants; the estimated pathogenicity odds ratio for exon 11 missense variants was below 0.01.
    → BP1 · strong Does not name this variant
    PMID 31911673 ↗
    Source detail
    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.

    Location Results, BRCA1 section; Table 1 and Table 2

    Context ClinVar-based retrospective analysis of BRCA1 and BRCA2 missense variants from transcript NM_007294.3, with regional Bayesian odds-ratio estimates.

Other recorded publications

  • Interlaboratory diagnostic validation of conformation-sensitive capillary electrophoresis for mutation scanning.
    Mattocks CJ et al. · 2010
    No paper-specific finding is recorded.
    PMID 20167696 ↗
  • Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
    No paper-specific finding is recorded.
    PMID 25741868 ↗
  • A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
    No paper-specific finding is recorded.
    PMID 26467025 ↗
  • Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification.
    Parsons MT et al. · 2019
    The paper describes the ENIGMA multifactorial Bayesian framework integrating clinical segregation and other evidence types across BRCA1 and BRCA2, but does not explicitly mention BRCA1 c.3800T>C or p.(L1267S) and provides no variant-specific segregation result.
    Does not name this variant
    PMID 31131967 ↗
    Quoted passage
    We have collated data from >40 clinical sites within ENIGMA and from other international clinical collaborators to conduct the largest application of the multifactorial likelihood model to missense and intronic variants in BRCA1 and BRCA2, providing quantitative variant classifications, and also scores for the component data types so as to demonstrate their relative contributions to the final posterior probability.

    Introduction, final paragraph

  • Functional Categorization of BRCA1 Variants of Uncertain Clinical Significance in Homologous Recombination Repair Complementation Assays.
    Bouwman P et al. · 2020
    The study tested 238 BRCA1 variants of uncertain significance using cisplatin-sensitivity, olaparib-sensitivity, and DR-GFP homologous-recombination-repair assays, but the supplied extraction does not explicitly mention c.3800T>C or p.(L1267S); ENIGMA Table 9 nevertheless uses this study as the governing calibrated source for the variant-specific BS3 Strong assignment.
    Does not name this variant
    PMID 32546644 ↗
    Quoted passage
    All known pathogenic variants of BRCA1 and BRCA2 analyzed lead to HRR deficiency.

    Introduction, paragraph 1; Results, Comparison of the results from the three functional assays

  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    No paper-specific finding is recorded.
    PMID 28492532 ↗

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

gnomAD v4.1 9 / 1,614,102 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.034 Open source ↗
ClinVar 5 Uncertain significance · 4 Likely benign · 1 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

This variant is present in gnomAD v4.1 (AF= 5.57586e-06; MAF= 0.00056%, 9/1614102 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.62687e-06; MAF= 0.00076%, 9/1180038 alleles, homozygotes = 0); grpmax FAF= 3.59e-06.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories) and as Likely benign (4 clinical laboratories) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 142031)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.513. BayesDel score = -0.178917.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Neutral; curated oncogenicity label: Likely Neutral.

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.