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BRCA1c.1222A>GBenign
Print report
Variant interpretation report

BRCA1 c.1222A>G, p.(Lys408Glu)

NM_007294.4:c.1222A>G NP_009225.1:p.(Lys408Glu) 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: 2
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 2
BS3Strong
BS3 · strong

Met, Strong: ENIGMA Table 9 pre-assigns BS3 Strong after a calibrated protein assay reported a likely neutral result of 0.04.

BP1Strong
BP1 · strong

Met, strong: residue 408 is outside all VCEP critical domains and SpliceAI max delta 0.035 is below the <=0.1 no-splicing threshold.

Recorded classification: Benign

Benign: ENIGMA assigns BS3 Strong and BP1 Strong, producing -8 benign points under its conflicting-evidence point system.

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
41 / 1,614,214 alleles

gnomAD v4.1: 41 / 1,614,214 alleles. Recorded AF 2.53994e-05. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.98705e-06; MAF= 0.00040%, 1/250812 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.83252e-06; MAF= 0.00088%, 1/113218 alleles, homozygotes = 0).

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
0.550 recorded score

Recorded REVEL score: 0.550. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied
ClinVar submissions
11 reported laboratory submissions

5 Uncertain significance · 4 Likely benign · 2 Benign. ClinVar API review status: criteria provided, conflicting classifications.

Context only ClinVar ↗
Functional evidence
Statement recorded

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

Applied · BS3 → OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV99066385, n = 1 times).

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: 2 met · 9 not met · 5 not assessed · 12 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

All three requested criteria are not applicable under the governing ENIGMA BRCA1/2 VCEP specification for this missense variant.

No PVS1 strength tier is assigned because PVS1 is not applicable; the full-strength literal "very strong" is therefore not relevant.

The exact variant-level multifactorial evidence is neutral: combined LR 1.8748372548618257, which is neither >=2.08 for PP4 nor <=0.48 for BP5.

No PS4 case-control statistic was available, and no PP5/BP6 expert-panel ClinVar classification exists for the exact variant.

For this missense variant, the single applicable computational path is REVEL; PP3 and BP4 are not met because the REVEL score is 0.55, below PP3 supporting >=0.644 and above BP4 supporting <=0.29.

BP7 is not applicable because the variant is missense, not synonymous or qualifying intronic.

The ENIGMA BRCA1 VCEP population rules govern this assessment and require non-cancer population datasets rather than default all-comers frequencies.

The variant is rare but observed in the governing gnomAD v2.1 non-cancer exome dataset at AF 4.2321593323345435e-06, below BA1 and BS1_Supporting thresholds; it is absent from the available gnomAD v3.1 non-cancer result.

No qualifying phenotyped individual observations support BS2, and gnomAD homozygote counts are not eligible substitutes under ENIGMA Table 8.

Met · 2

BS3 StrongMet, Strong: ENIGMA Table 9 pre-assigns BS3 Strong after a calibrated protein assay reported a likely neutral result of 0.04. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA1 Specifications Table 9 contains an exact match for c.1222A>G (p.Lys408Glu; p.K408E) and pre-assigns BS3 Strong. It states that one calibrated study reported protein function similar to benign control variants, with a reported functional result of 0.04, no predicted splicing effect, and a likely neutral interpretation. Under the ENIGMA specification, this calibrated protein-only functional result meets BS3 Strong. No conflicting calibrated functional result for this variant was identified in the searched VCEP materials.

Rule
ENIGMA BRCA1 v1.2 Table 9 exact-variant pre-assignment: BS3 Strong.
Evidence considered
  • ENIGMA BRCA1 Specifications Table 9 exact row: BRCA1 c.1222A>G, p.(Lys408Glu), assigned code BS3, code weight Strong.
  • The governing Table 9 text states: "Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID:32546644) (BS3 met)."
  • The row reports a functional result of 0.04, no predicted splicing effect (N), one publication, and Bouwman 2020 (PMID:32546644) interpreted as likely neutral.
  • The ENIGMA v1.2 functional-assay rule specifies BS3 Strong for well-established protein-function studies showing no damaging effect, with calibrated variant-specific recommendations taken from Table 9.
Still missing
  • The case has no paper_extracts.json or fetched publication entry for PMID:32546644, so the primary paper's detailed assay design, controls, and replicate data were not independently reviewed beyond the governing VCEP Table 9 summary.
  • SupplementaryTables_V1.2_2024-11-18.xlsx.txt contains no exact entry for c.1222A>G, p.Lys408Glu, or p.K408E; its searched ST4 functional rows therefore do not add variant-specific assay detail.
  • HUMU-40-1557-s001.xlsx.txt contains an exact c.1222A>G / p.(Lys408Glu) row but no functional assay result or functional code assignment for this variant.
Sources
vcep_specifications_table9_v1_2_2024_11_18cspec ↗
BP1 StrongMet, strong: residue 408 is outside all VCEP critical domains and SpliceAI max delta 0.035 is below the <=0.1 no-splicing threshold. Details ▾Hide ▴
Reasoning

BP1_Strong is met. The ENIGMA BRCA1 VCEP applies BP1_Strong to missense variants outside a potentially clinically important functional domain when no splicing is predicted (SpliceAI <=0.1). p.Lys408Glu is at residue 408, outside the VCEP-defined RING domain (aa 2-101), coiled-coil domain (aa 1391-1424), and BRCT repeats (aa 1650-1857). SpliceAI max delta is 0.035, satisfying the no-predicted-splicing condition. Independent literature extraction also places residue 408 in BRCA1 exon 11, a missense coldspot with estimated odds ratio for pathogenicity <0.01, consistent with benign regional context, although the VCEP rule is the governing assignment.

Rule
ENIGMA BRCA1 V1.2 BP1_Strong: missense or in-frame variant outside a potentially clinically important functional domain and no predicted splicing (SpliceAI <=0.1).
Evidence considered
  • ENIGMA BRCA1 V1.2 BP1_Strong requires an outside-domain missense or in-frame variant and no predicted splicing, defined as SpliceAI <=0.1.
  • Residue 408 is outside the VCEP domains RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857.
  • The case SpliceAI max delta is 0.035, below the VCEP threshold of <=0.1.
  • The coldspot study reports that BRCA1 exon 11 has no confirmed pathogenic or likely pathogenic missense variants and an estimated odds ratio for pathogenicity of <0.01; residue 408 lies within this exon 11 region.
Still missing
  • Specifications_Table4_V1.2_2024-11-18.xlsx: no entry for c.1222A>G, p.Lys408Glu, or p.K408E.
  • SupplementaryTables_V1.2_2024-11-18.xlsx: no entry for c.1222A>G, p.Lys408Glu, or p.K408E.
  • Specifications_V1.2_2024-11-18.docx: no entry for c.1222A>G, p.Lys408Glu, or p.K408E.
  • Appendices_V1.2_2024-11-18.docx: no entry for c.1222A>G, p.Lys408Glu, or p.K408E.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18PMID:31911673 ↗

Not met · 9 · evaluated, threshold not reached

PS1 Not met: SpliceAI max delta is 0.035, but no qualifying previously pathogenic same-amino-acid comparator was found. Details ▾Hide ▴
Reasoning

PS1 is not met. The ENIGMA BRCA1 VCEP requires a previously established pathogenic or likely pathogenic variant producing the same missense amino-acid substitution, with no confirmed or predicted splice effect (SpliceAI <=0.1). Searches of the governing Specifications_V1.2_2024-11-18.docx, SupplementaryTables_V1.2_2024-11-18.xlsx, Appendices_V1.2_2024-11-18.docx, and Specifications_Table4_V1.2_2024-11-18.xlsx found no entry for c.1222A>G, p.Lys408Glu, or p.K408E and no qualifying pathogenic same-amino-acid comparator. The case variant is missense with SpliceAI max delta 0.035, but the required pathogenic comparator is absent.

Rule
ENIGMA BRCA1 V1.2 PS1: same missense amino-acid substitution as a previously established pathogenic or likely pathogenic variant; for protein-change PS1, no confirmed or predicted splice effect (SpliceAI <=0.1).
Evidence considered
  • ENIGMA BRCA1 VCEP PS1 requires a previously classified pathogenic or likely pathogenic variant with the same predicted missense substitution; pathogenic references must be evaluated under VCEP specifications.
  • The case variant is missense and has SpliceAI max delta 0.035, below the VCEP no-predicted-splicing threshold of <=0.1.
  • No qualifying pathogenic same-amino-acid comparator was found in the searched governing VCEP files.
Still missing
  • Specifications_V1.2_2024-11-18.docx: no entry for c.1222A>G, p.Lys408Glu, or p.K408E.
  • SupplementaryTables_V1.2_2024-11-18.xlsx: no entry for c.1222A>G, p.Lys408Glu, or p.K408E.
  • Appendices_V1.2_2024-11-18.docx: no entry for c.1222A>G, p.Lys408Glu, or p.K408E.
  • Specifications_Table4_V1.2_2024-11-18.xlsx: no entry for c.1222A>G, p.Lys408Glu, or p.K408E.
Sources
cspec ↗
PS3 Not met: ENIGMA Table 9 assigns BS3 Strong, with calibrated protein-function result 0.04 classified as likely neutral rather than damaging. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA1 Table 9 entry for c.1222A>G (p.Lys408Glu; p.K408E) assigns BS3 Strong, not PS3, stating that one calibrated study reported protein function similar to benign control variants. The reported assay result is 0.04 and is classified as likely neutral. Therefore, the available calibrated functional evidence supports absence of damaging protein impact rather than PS3. No conflicting calibrated functional result for this variant was identified in the searched VCEP materials.

Rule
ENIGMA BRCA1 v1.2 Table 9 pre-assignment governs calibrated protein-function evidence; PS3 applies to damaging results, whereas this exact variant is assigned BS3 Strong.
Evidence considered
  • ENIGMA BRCA1 Specifications Table 9 contains an exact c.1222A>G / p.(Lys408Glu) row assigning BS3 Strong.
  • The Table 9 standardized text states: "Reported by one calibrated study to exhibit protein function similar to benign control variants (PMID:32546644) (BS3 met)."
  • The same Table 9 row reports the functional result as 0.04, with no predicted splicing effect (N) and one publication, Bouwman 2020 (PMID:32546644), interpreted as likely neutral.
  • The ENIGMA v1.2 specification states that PS3 is for calibrated functional assays showing a damaging effect, while BS3 Strong is for well-established protein-function assays showing no damaging effect; its Table 9 is the governing lookup for these calibrated results.
Still missing
  • No PS3 pre-assignment was found for c.1222A>G, p.Lys408Glu, or p.K408E in Specifications_Table9_V1.2_2024-11-18.xlsx.txt; the governing entry assigns BS3 Strong instead.
  • The case has no paper_extracts.json or fetched publication entry for PMID:32546644, so assay-specific details beyond the VCEP Table 9 summary and its reported result value were not independently reviewed.
Sources
vcep_specifications_table9_v1_2_2024_11_18cspec ↗
PM1 Not met: Lys408 lies outside BRCA1 RING 2-101, coiled-coil 1391-1424, and BRCT 1650-1857, and VCEP PM1 is not used. Details ▾Hide ▴
Reasoning

PM1 is not met. The governing ENIGMA BRCA1 VCEP explicitly specifies PM1 as not used and instead considers hotspot/domain information within bioinformatic analysis. The case residue is Lys408, outside the authoritative domain_tables list, which is empty; the VCEP domain definitions place BRCA1 critical or potentially critical domains at RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857. Lys408 is in none of these domains, and the VCEP does not authorize standalone PM1.

Rule
ENIGMA BRCA1 V1.2 PM1: Do not use; critical-domain and hotspot information is considered within PP3/BP4 bioinformatic analysis.
Evidence considered
  • The ENIGMA BRCA1 VCEP Table 1 specification states PM1 is not used and that hotspot/domain information is considered as part of bioinformatic analysis.
  • The VCEP-defined BRCA1 domains are RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857; residue 408 is outside all three.
  • vcep_materials.json has an empty domain_tables object, so no additional authoritative gene-specific domain entry applies.
Still missing
  • Specifications_V1.2_2024-11-18.docx: no entry for c.1222A>G, p.Lys408Glu, or p.K408E.
  • SupplementaryTables_V1.2_2024-11-18.xlsx: no entry for c.1222A>G, p.Lys408Glu, or p.K408E.
  • Appendices_V1.2_2024-11-18.docx: no entry for c.1222A>G, p.Lys408Glu, or p.K408E.
  • Specifications_Table4_V1.2_2024-11-18.xlsx: no entry for c.1222A>G, p.Lys408Glu, or p.K408E.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PM2 Not met: the variant is present at AF 4.23e-06 in gnomAD v2.1 non-cancer exomes, so ENIGMA PM2 absence from both datasets is not satisfied. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA1 VCEP specifies PM2_Supporting only when the variant is absent from both gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, with average regional read depth at least 25. The variant is present in gnomAD v2.1 non-cancer exomes at AF 4.2321593323345435e-06 (1/236286 alleles), although absent from the available gnomAD v3.1 non-cancer result; therefore the required absence from both specified datasets is not met.

Rule
ENIGMA PM2_Supporting: variant must be absent from gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, with regional average read depth >=25.
Evidence considered
  • ENIGMA BRCA1 VCEP specifies PM2_Supporting for absence from gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, with regional average read depth >=25.
  • The case evidence reports the variant present in gnomAD v2.1 non-cancer exomes at AF 4.2321593323345435e-06, with 1 alternate allele among 236286 alleles and 0 homozygotes.
  • The case evidence reports the variant absent from gnomAD v3.1 non-cancer, but presence in the required v2.1 non-cancer dataset prevents PM2 application.
  • The ENIGMA Supplementary Tables ST8 frequency-LR table was searched for the variant notations c.1222A>G, p.Lys408Glu, and p.K408E; no variant-specific ST8 row was found.
Still missing
  • The supplied evidence does not report the average regional read depth required by the ENIGMA PM2 rule; this does not change the conclusion because the variant is observed in gnomAD v2.1 non-cancer exomes.
Sources
cspec ↗gnomad_v2 ↗vcep_supplementarytables_v1_2_2024_11_18
PP2 Not met: ENIGMA explicitly disallows PP2 for BRCA1 because the gene has a high frequency of benign missense variation. Details ▾Hide ▴
Reasoning

PP2 is not met. The governing ENIGMA BRCA1 VCEP explicitly specifies PP2 as not used because BRCA1 has a high frequency of benign missense variation. Therefore, this missense variant cannot receive PP2 under the applicable gene-specific framework, regardless of its residue or amino-acid substitution.

Rule
ENIGMA BRCA1 V1.2 PP2: Do not use; high frequency of benign missense variants.
Evidence considered
  • The ENIGMA BRCA1 VCEP Table 1 entry for PP2 states Do not use and gives high frequency of benign missense variants as the reason.
  • The case variant is a BRCA1 missense substitution, but the gene-specific exclusion prevents PP2 application.
Still missing
  • Specifications_V1.2_2024-11-18.docx: no entry for c.1222A>G, p.Lys408Glu, or p.K408E.
  • SupplementaryTables_V1.2_2024-11-18.xlsx: no entry for c.1222A>G, p.Lys408Glu, or p.K408E.
  • Appendices_V1.2_2024-11-18.docx: no entry for c.1222A>G, p.Lys408Glu, or p.K408E.
  • Specifications_Table4_V1.2_2024-11-18.xlsx: no entry for c.1222A>G, p.Lys408Glu, or p.K408E.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PP3 Not met: missense REVEL 0.55 is below the ClinGen SVI supporting PP3 threshold of 0.644. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, so the missense protein-impact path applies and SpliceAI is not used for PP3/BP4. No governing ENIGMA row assigning PP3 was found for c.1222A>G, p.Lys408Glu, or p.K408E in the searched supplementary tables, specification document, appendices, or Houdayer full text. The case REVEL score is 0.55, below the published ClinGen SVI supporting PP3 threshold of 0.644 (Pejaver et al. 2022, PMID:36413997), so PP3 is not met. The ENIGMA BRCA1 specification also requires BayesDel no-AF >=0.28 for its missense protein-impact PP3 route and limits that route to a clinically important functional domain; p.Lys408Glu is outside the listed BRCA1 RING, coiled-coil, and BRCT domains, and the available BayesDel score is -0.10342.

Rule
Missense variant: use REVEL only for this group's computational protein-impact assessment; PP3 supporting requires REVEL >=0.644 under the published ClinGen SVI calibration. ENIGMA BRCA1 v1.2 additionally specifies BayesDel no-AF >=0.28 and a listed clinically important domain for its missense PP3 route.
Evidence considered
  • The case normalization identifies NM_007294.4:c.1222A>G as the missense variant NP_009225.1:p.(Lys408Glu), p.(K408E), so the missense REVEL path is applicable and BP7 is not.
  • The local REVEL lookup reports a score of 0.55 for this variant.
  • ClinGen SVI REVEL calibration defines supporting PP3 at REVEL >=0.644; Pejaver et al. 2022, PMID:36413997.
  • ENIGMA BRCA1 v1.2 specifies the missense protein-impact PP3 route using BayesDel no-AF >=0.28 within a clinically important functional domain; its listed BRCA1 domains are RING aa 2-101, coiled-coil aa 1391-1424, and BRCT aa 1650-1857, while p.Lys408Glu is outside these domains.
  • The available BayesDel no-AF score is -0.10342, below the ENIGMA PP3 threshold, and no governing VCEP PP3 lookup row was found for this variant after searching c.1222A>G, p.Lys408Glu, and p.K408E.
Still missing
  • No PP3, BP4, or BP7 assignment for c.1222A>G, p.Lys408Glu, or p.K408E was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No PP3, BP4, or BP7 assignment for c.1222A>G, p.Lys408Glu, or p.K408E was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No PP3, BP4, or BP7 assignment for c.1222A>G, p.Lys408Glu, or p.K408E was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No PP3, BP4, or BP7 assignment for c.1222A>G, p.Lys408Glu, or p.K408E was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗revel
BA1 Not met: gnomAD v2.1 non-cancer exome AF 4.23e-06 is below the ENIGMA BA1 threshold of 0.001. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA1 VCEP specifies BA1 when the maximum filter allele frequency exceeds 0.001 (0.1%) in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer non-founder populations. The variant is present in gnomAD v2.1 non-cancer exomes at AF 4.2321593323345435e-06 (1/236286 alleles; homozygotes 0), far below 0.001. The available gnomAD v3.1 non-cancer result is absent, but that does not establish BA1.

Rule
ENIGMA BA1: apply when maximum filter allele frequency is >0.001 in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer non-founder populations.
Evidence considered
  • ENIGMA BRCA1 VCEP v1.2 specifies BA1 for filter allele frequency >0.001 in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer non-founder populations.
  • The case evidence reports gnomAD v2.1 non-cancer exome AF 4.2321593323345435e-06, with 1 alternate allele among 236286 alleles and 0 homozygotes.
  • The case evidence reports the variant as absent from gnomAD v3.1 non-cancer; the available frequency evidence does not reach the BA1 threshold.
Sources
cspec ↗gnomad_v2 ↗
BS1 Not met: gnomAD v2.1 non-cancer exome AF 4.23e-06 is below the ENIGMA BS1-supporting lower threshold of 0.00002. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA1 VCEP specifies BS1 when filter allele frequency exceeds 0.0001 (0.01%) and BS1_Supporting when it is >0.00002 and <=0.0001 in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer non-founder populations. The variant's gnomAD v2.1 non-cancer exome AF is 4.2321593323345435e-06, below 0.00002, and the gnomAD v3.1 non-cancer result is absent.

Rule
ENIGMA BS1: apply BS1 when filter allele frequency is >0.0001; apply BS1_Supporting when it is >0.00002 and <=0.0001 in the specified non-cancer gnomAD populations.
Evidence considered
  • ENIGMA BRCA1 VCEP specifies BS1 for filter allele frequency >0.0001 and BS1_Supporting for >0.00002 to <=0.0001 in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer non-founder populations.
  • The case evidence reports gnomAD v2.1 non-cancer exome AF 4.2321593323345435e-06 (1/236286 alleles; homozygotes 0), which is below 0.00002.
  • The case evidence reports the variant as absent from gnomAD v3.1 non-cancer, providing no additional frequency that reaches a BS1 threshold.
Sources
cspec ↗gnomad_v2 ↗
BP4 Not met: missense REVEL 0.55 exceeds the ClinGen SVI supporting BP4 threshold of <=0.29. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, so the missense protein-impact path applies and SpliceAI is not used for BP4. No governing ENIGMA row assigning BP4 was found for c.1222A>G, p.Lys408Glu, or p.K408E in the searched supplementary tables, specification document, appendices, or Houdayer full text. The case REVEL score is 0.55, above the published ClinGen SVI supporting BP4 threshold of <=0.29 (Pejaver et al. 2022, PMID:36413997), placing it outside the benign-supporting range; the gray-zone result does not permit substitution of the SpliceAI score. The ENIGMA BRCA1 missense BP4 rule also requires no protein impact by BayesDel and no splice impact within a clinically important functional domain, whereas p.Lys408Glu is outside the listed domains and the BayesDel score is -0.10342.

Rule
Missense variant: use REVEL only for this group's computational protein-impact assessment; BP4 supporting requires REVEL <=0.29 under the published ClinGen SVI calibration. A gray-zone REVEL result does not permit substitution of SpliceAI.
Evidence considered
  • The case normalization identifies NM_007294.4:c.1222A>G as the missense variant NP_009225.1:p.(Lys408Glu), p.(K408E), so the missense REVEL path is applicable and SpliceAI is not used for BP4.
  • The local REVEL lookup reports a score of 0.55 for this variant.
  • ClinGen SVI REVEL calibration defines supporting BP4 at REVEL <=0.29; Pejaver et al. 2022, PMID:36413997.
  • ENIGMA BRCA1 v1.2 specifies the missense BP4 route with BayesDel no-AF <=0.15 and SpliceAI <=0.1 within a clinically important functional domain; its listed BRCA1 domains are RING aa 2-101, coiled-coil aa 1391-1424, and BRCT aa 1650-1857, while p.Lys408Glu is outside these domains.
  • The available BayesDel no-AF score is -0.10342, but the REVEL result is not within the calibrated BP4 range; the missense gray-zone result does not license using the available SpliceAI max delta of 0.035 as BP4 support.
Still missing
  • No PP3, BP4, or BP7 assignment for c.1222A>G, p.Lys408Glu, or p.K408E was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No PP3, BP4, or BP7 assignment for c.1222A>G, p.Lys408Glu, or p.K408E was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No PP3, BP4, or BP7 assignment for c.1222A>G, p.Lys408Glu, or p.K408E was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No PP3, BP4, or BP7 assignment for c.1222A>G, p.Lys408Glu, or p.K408E was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗revel

Not assessed · 5 · no assessment recorded

PS4 Not assessed: no exact-variant case-control OR, confidence interval, or p-value was available to evaluate the PS4 thresholds (p <=0.05 and OR >=4). Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 specification requires case-control evidence with p-value <=0.05, OR >=4, and a lower confidence limit excluding 2.0 for PS4 Strong. No exact c.1222A>G/p.Lys408Glu/p.K408E case-control OR, confidence interval, or p-value was identified in the consulted case evidence or governing VCEP materials. The ENIGMA specification also states that proband counting should not be used; therefore PS4 cannot be assessed from the available evidence.

Rule
PS4 Strong: case-control p-value <=0.05 and OR >=4, with the lower confidence interval excluding 2.0.
Evidence considered
  • The ENIGMA rule states: 'Case-control studies; p-value <=0.05 and OR >=4 (lower confidence interval excludes 2.0).'
  • The ENIGMA instructions state that proband counting as originally described should not be used.
Still missing
  • No exact c.1222A>G, p.Lys408Glu, or p.K408E entry was found in Specifications_V1.2_2024-11-18.docx.txt; its PS4 rule was consulted.
  • No exact-variant case-control odds ratio, confidence interval, or p-value was available.
Sources
cspec ↗
PM3 Not assessed: the variant has no documented Fanconi-anemia phenotype, pathogenic partner, or qualifying trans-phase proband evidence needed for ENIGMA PM3 points. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 VCEP specification restricts PM3 to patients with a phenotype consistent with BRCA1- or BRCA2-related Fanconi anemia and co-occurring pathogenic or likely pathogenic variants in the same gene; PM3 strength is based on the Table 6 point total (Supporting = 1, Moderate = 2, Strong = 4 or more). The exact-variant row for BRCA1 c.1222A>G / p.(Lys408Glu) in the ENIGMA HUMU-40-1557 dataset reports a co-occurrence likelihood ratio of 1.2975141811 and a combined likelihood ratio of 1.8748372548618257, but it does not document a pathogenic/likely pathogenic partner, trans phase, an affected proband with BRCA1-related Fanconi anemia, chromosome-breakage findings, or the required clinical features. Therefore, no PM3 points can be assigned from the available evidence.

Rule
ENIGMA BRCA1/2 VCEP PM3_VariableWeight: apply only for a patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi anemia and co-occurring variants in the same gene; PM3_Supporting = 1 point, PM3 = 2 points, PM3_Strong = 4 or more points. A pathogenic/likely pathogenic variant in trans is required for the 2-point observation; phase unknown receives 1 point.
Evidence considered
  • ENIGMA BRCA1/2 VCEP v1.2 requires a Fanconi-anemia-consistent phenotype plus a same-gene pathogenic or likely pathogenic co-occurring variant; Table 6 assigns PM3 points of 1 for phase unknown and 2 for a pathogenic/likely pathogenic variant in trans per qualifying proband, with final PM3 strength based on the summed points.
  • The exact HUMU-40-1557-s001 row for BRCA1 c.1222A>G / p.(Lys408Glu) reports co-occurrence LR 1.2975141811 and combined LR 1.8748372548618257, but supplies no individual-level phase, partner classification, or Fanconi-anemia phenotype details.
  • The exact variant notations c.1222A>G, p.Lys408Glu, and p.K408E were searched in Specifications_V1.2_2024-11-18.docx.txt; no variant-specific PM3 assignment was found there.
Still missing
  • No affected proband with a phenotype meeting the ENIGMA BRCA1/2 Fanconi-anemia definition was identified for c.1222A>G / p.(Lys408Glu).
  • No pathogenic or likely pathogenic BRCA1 co-occurring variant with documented trans phase was identified for this variant.
  • The exact-variant entry in HUMU-40-1557-s001 reports co-occurrence and combined likelihood ratios but does not provide the individual-level phase, partner classification, or Fanconi-anemia clinical and chromosome-breakage details required for PM3.
  • No entry for c.1222A>G, p.Lys408Glu, or p.K408E was found in Specifications_V1.2_2024-11-18.docx.txt beyond the general PM3 rule and Table 6; that file was searched explicitly.
Sources
cspec ↗vcep_humu_40_1557_s001
PP1 Not assessed: the exact-variant VCEP row has no segregation LR, so PP1's supporting threshold of LR ≥2.08:1 cannot be evaluated. Details ▾Hide ▴
Reasoning

ENIGMA v1.2 requires PP1 to be based on co-segregation with disease in multiple affected family members, quantified by a co-segregation likelihood ratio: 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. The exact-variant row for BRCA1 c.1222A>G / p.(Lys408Glu) / K408E in HUMU-40-1557-s001 contains no segregation LR, and the case evidence bundle provides no proband, parental-testing, pedigree, affected-relative, or meiosis data; therefore PP1 cannot be assigned.

Rule
ENIGMA BRCA1/2 v1.2 PP1 variable weight: assign only from quantitative co-segregation LR; PP1 supporting requires LR ≥2.08:1.
Evidence considered
  • Specifications_V1.2-2024-11-18.docx, PP1: co-segregation with disease in multiple affected family members, quantified by Bayes-score likelihood ratio; thresholds are supporting ≥2.08:1, moderate ≥4.3:1, strong ≥18.7:1, and very strong ≥350:1.
  • HUMU-40-1557-s001 exact-variant row: BRCA1 c.1222A>G, p.(Lys408Glu), K408E; segregation LR is blank, while the row records combined LR 1.8748372548618257 and states that the combined LR is not <0.5 or >2 and is not informative.
  • The case evidence bundle contains no variant-specific proband, parental-testing, pedigree, affected-relative, or meiosis observations usable for PP1.
Still missing
  • No variant-specific proband, parental-testing, pedigree, affected-relative, or meiosis data are available for quantitative PP1 assessment.
  • HUMU-40-1557-s001 was searched and contains the exact variant row, but its segregation LR field is blank.
Sources
vcep_specifications_v1_2_2024_11_18vcep_humu_40_1557_s001
BS2 Not assessed: gnomAD shows zero homozygotes, but no qualifying phenotyped healthy-adult observations or ENIGMA BS2 point total is available. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP applies BS2 using point-scored observations of the variant in phenotyped individuals who are healthy or have late-onset cancer, including documented phase with a pathogenic or likely pathogenic BRCA1 variant, and in the absence of Fanconi Anemia features. Table 8 explicitly excludes homozygote observations from gnomAD frequency data because those observations are captured by BA1 or BS1. The available case evidence reports zero gnomAD homozygotes and contains no qualifying phenotyped individual observations or BS2 point total.

Rule
ENIGMA BS2: assign strength from the Table 8 point total for qualifying phenotyped individuals; do not use gnomAD frequency-data homozygotes as BS2 observations.
Evidence considered
  • ENIGMA BRCA1 VCEP Table 8 assigns BS2 from point-scored phenotyped individuals based on age at cancer diagnosis or age at last follow-up, phase/co-occurrence, and absence of Fanconi Anemia features.
  • ENIGMA Table 8 states that homozygote observations in gnomAD are not used for BS2 because they are already captured by BA1 or BS1 frequency codes.
  • The case evidence reports zero homozygotes in gnomAD v2.1 non-cancer exomes and provides no qualifying phenotyped individual observations or BS2 point total.
Still missing
  • No qualifying phenotyped healthy-adult or late-onset individual observations with sufficient clinical follow-up and phase information were identified in the supplied case evidence.
  • No ENIGMA BS2 point total is available; gnomAD homozygote counts cannot substitute for the required phenotyped observations.
Sources
cspec ↗gnomad_v2 ↗vcep_appendices_v1_2_2024_11_18
BS4 Not assessed: the exact-variant VCEP row has no segregation LR, while its combined LR 1.8748 is non-informative and cannot establish BS4. Details ▾Hide ▴
Reasoning

ENIGMA v1.2 requires BS4 to show lack of segregation in affected family members using a quantitative co-segregation likelihood ratio: 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. The exact-variant row for BRCA1 c.1222A>G / p.(Lys408Glu) / K408E in HUMU-40-1557-s001 contains no segregation LR, and the case evidence bundle provides no affected-family non-segregation or parental-testing data. The reported combined LR of 1.8748372548618257 is explicitly non-informative and is not a BS4-specific segregation LR, so BS4 cannot be assigned.

Rule
ENIGMA BRCA1/2 v1.2 BS4 variable weight: assign only from quantitative lack-of-segregation LR; BS4 supporting requires LR ≤0.48:1.
Evidence considered
  • Specifications_V1.2-2024-11-18.docx, BS4: lack of segregation in affected family members, quantified by Bayes-score likelihood ratio; thresholds are supporting ≤0.48:1, moderate ≤0.23:1, strong ≤0.05:1, and very strong ≤0.00285:1.
  • HUMU-40-1557-s001 exact-variant row: BRCA1 c.1222A>G, p.(Lys408Glu), K408E; segregation LR is blank, and the combined LR 1.8748372548618257 is labeled not informative because it is not <0.5 or >2.
  • The case evidence bundle contains no variant-specific affected-family non-segregation, parental-testing, pedigree, or meiosis observations usable for BS4.
Still missing
  • No variant-specific affected-family non-segregation, parental-testing, pedigree, or meiosis data are available for quantitative BS4 assessment.
  • HUMU-40-1557-s001 was searched and contains the exact variant row, but its segregation LR field is blank.
Sources
vcep_specifications_v1_2_2024_11_18vcep_humu_40_1557_s001
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: c.1222A>G is missense, p.(Lys408Glu), not an ENIGMA PVS1 null-variant class. Details ▾Hide ▴
Reasoning

NM_007294.4:c.1222A>G is a missense variant, NP_009225.1:p.(Lys408Glu) (p.(K408E)), rather than a nonsense, frameshift, canonical +/-1,2 splice, initiation-codon, or exon-deletion null variant. The ENIGMA BRCA1 specification limits PVS1 to null variants and mRNA-only damaging studies, with Table 4 governing the null-variant decision tree; the variant has no entry in the searched Table 4 text under c.1222A>G, p.Lys408Glu, or p.K408E. Therefore PVS1 is not applicable despite BRCA1 loss of function being an established disease mechanism.

Rule
ENIGMA PVS1 applies to specified null variants or qualifying mRNA-only damaging evidence; a missense variant without such a qualifying consequence is not applicable.
Evidence considered
  • The case consequence annotation identifies NM_007294.4:c.1222A>G as missense, encoding NP_009225.1:p.(Lys408Glu) (p.(K408E)).
  • ENIGMA BRCA1/2 Specification v1.2 defines PVS1 for null variants and directs application through the exon-specific PVS1 decision tree in Table 4.
  • The required searches of the full Table 4 text for c.1222A>G, p.Lys408Glu, and p.K408E found no variant-specific entry.
Still missing
  • No c.1222A>G, p.Lys408Glu, or p.K408E entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt; this table governs null-variant PVS1 decisions.
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18
PS2 VCEPNot applicable: the ENIGMA specification explicitly says PS2 should not be used because de novo occurrences lack calibrated predictive value for BRCA1/2 cancers. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA1/2 specification v1.2 explicitly states that PS2 (de novo, paternity confirmed, in a patient with disease and no family history) should not be used because BRCA1/2-related cancers are relatively common and there is no calibrated information on the predictive capacity of de novo occurrences.

VCEP rule
ENIGMA BRCA1/2 v1.2: PS2 is not to be used.
Evidence considered
  • Specifications_V1.2_2024-11-18.docx, PS2: ‘De novo (paternity confirmed) in a patient with the disease and no family history’; application: ‘Do not use’.
  • The same specification explains that BRCA1/2-related cancers occur relatively commonly and that there is no information to calibrate the predictive capacity of de novo occurrences.
Sources
vcep_specifications_v1_2_2024_11_18
PM4 VCEPNot applicable: p.(Lys408Glu) is a missense substitution with no protein-length change, and ENIGMA explicitly does not use PM4. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 Specification v1.2 explicitly designates PM4 as not applicable and states that protein-length changes due to in-frame deletions/insertions in non-repeat regions or stop-loss variants are instead considered within bioinformatic analysis. This variant is a single amino-acid missense substitution, not an in-frame insertion, in-frame deletion, delins, or stop-loss variant, and no protein-length change is present.

VCEP rule
ENIGMA BRCA1/2 PM4: Do not use; protein-length changes are considered as part of bioinformatic analysis.
Evidence considered
  • The case annotation identifies p.(Lys408Glu), a missense substitution with unchanged protein length.
  • ENIGMA Specification v1.2 Table 1 states that PM4 is not applicable and covers protein-length changes due to in-frame insertions/deletions or stop-loss variants.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PM5 N/ANot applicable: c.1222A>G is missense, whereas ENIGMA PM5 is reserved for exon-specific protein-termination-codon variants. Details ▾Hide ▴
Reasoning

PM5 is not applicable to this missense variant under the governing ENIGMA BRCA1 VCEP. The VCEP explicitly says classic missense PM5 is not used and repurposes PM5 only as PM5_VariableWeight (PTC) for protein-termination-codon variants in specified exons. c.1222A>G, p.Lys408Glu is a missense substitution, not a PTC or truncating variant. The governing Table 4 and ST1 PM5_PTC materials therefore do not provide a relevant assignment.

Rule
ENIGMA BRCA1 V1.2 PM5: classic missense PM5 is not used; PM5_VariableWeight (PTC) applies only to genomic protein-termination-codon variants and is weighted by exon.
Evidence considered
  • ENIGMA BRCA1 V1.2 states classic missense PM5 is not used and defines PM5_VariableWeight (PTC) only for protein-termination-codon variants.
  • The case consequence is missense, with protein change p.(Lys408Glu), so the PTC-specific PM5 rule cannot apply.
  • The collected PM5 candidate artifact reports no classic same-residue candidates and identifies the VCEP PM5 mode as PTC-specific.
Still missing
  • Specifications_Table4_V1.2_2024-11-18.xlsx: no entry for c.1222A>G, p.Lys408Glu, or p.K408E.
  • SupplementaryTables_V1.2_2024-11-18.xlsx: no entry for c.1222A>G, p.Lys408Glu, or p.K408E.
  • Specifications_V1.2_2024-11-18.docx: no entry for c.1222A>G, p.Lys408Glu, or p.K408E.
  • Appendices_V1.2_2024-11-18.docx: no entry for c.1222A>G, p.Lys408Glu, or p.K408E.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18
PM6 VCEPNot applicable: the governing ENIGMA BRCA1/2 framework marks PM6 as not applicable, regardless of any unconfirmed de novo observation. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA1/2 framework marks PM6 as not applicable. No alternative VCEP rule authorizes PM6 for this BRCA1 variant, so generic PM6 de novo evidence is not applied.

VCEP rule
ENIGMA BRCA1/2 v1.2 framework: PM6 not applicable.
Evidence considered
  • The governing ENIGMA BRCA1/2 framework's structured PM6 entry is ‘Not Applicable’; no VCEP-specific PM6 application rule is provided for this variant.
Sources
vcep_specifications_v1_2_2024_11_18
PP4 N/ANot applicable: combined clinical LR 1.8748372548618257 >= 2.08? no, placing it within ENIGMA's neutral PP4 interval. Details ▾Hide ▴
Reasoning

The exact BRCA1 c.1222A>G/p.(Lys408Glu)/K408E row reports a combined LR of 1.8748372548618257 and explicitly says the combined LR is not <0.5 or >2. The governing ENIGMA PP4 thresholds require LR >=2.08 for Supporting, >=4.3 for Moderate, >=18.7 for Strong, or >=350 for Very Strong. The decisive comparison is 1.8748372548618257 >= 2.08? no; it is within the ENIGMA neutral interval >0.48 and <2.08, for which PP4 is not applicable.

Rule
PP4 uses combined clinical LR: Supporting >=2.08:1; Moderate >=4.3:1; Strong >=18.7:1; Very Strong >=350:1. Combined LR >0.48 and <2.08 is not informative.
Evidence considered
  • The exact clinical-history LR row reports combined LR 1.8748372548618257 and states: 'Combined LR is not <0.5 or >2'.
  • The ENIGMA PP4 rule requires LR >=2.08 for Supporting, >=4.3 for Moderate, >=18.7 for Strong, or >=350 for Very Strong; combined LR >0.48 and <2.08 is not informative and PP4 is not applicable.
Still missing
  • No exact c.1222A>G, p.Lys408Glu, or p.K408E entry was found in Specifications_V1.2_2024-11-18.docx.txt; its PP4 rule was consulted.
Sources
vcep_pmid_31853058_brca1_clinical_history_lrvcep_humu_40_1557_s001cspec ↗PMID:31853058 ↗PMID:17924331 ↗
PP5 VCEPNot applicable: ClinVar has zero expert-panel submissions for the exact variant, so ordinary laboratory labels cannot trigger PP5. Details ▾Hide ▴
Reasoning

The exact ClinVar record for NM_007294.4:c.1222A>G (p.Lys408Glu) has no expert-panel submission and is classified as conflicting/uncertain with ordinary laboratory submissions only. The ENIGMA VCEP specification marks PP5 as not applicable for this VCEP. Under the required expert-panel-only rule, no PP5 evidence can be applied.

VCEP rule
Apply PP5 only for an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification; ordinary laboratory submissions and aggregate labels do not qualify.
Evidence considered
  • The exact ClinVar submission audit counts expert_panel_submissions as 0 and usable_for_classification as 0.
  • The ENIGMA VCEP rule states: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.'
Sources
clinvar ↗cspec ↗
BP2 VCEPNot applicable: ENIGMA explicitly prohibits BP2 for BRCA1/2 and permits it only in the context of BS2. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA1/2 VCEP specification explicitly states that BP2 is not used and is applied only in the context of BS2. The same rule is reproduced in the case's VCEP framework: observed-in-trans with a pathogenic variant for a fully penetrant dominant disorder, or observed-in-cis with a pathogenic variant in any inheritance pattern, is not an applicable BRCA1 criterion. Accordingly, BP2 is not assessed for this variant even though the available exact-variant HUMU-40-1557 row reports a co-occurrence likelihood ratio.

VCEP rule
ENIGMA BRCA1/2 VCEP BP2: Do not use; applied only in the context of BS2.
Evidence considered
  • ENIGMA BRCA1/2 VCEP v1.2 Table 1 specifies BP2 as 'Do not use' and states that it is applied only in the context of BS2.
Sources
cspec ↗
BP3 VCEPNot applicable: c.1222A>G is missense, not an in-frame insertion/deletion, and ENIGMA explicitly does not use BP3. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 Specification v1.2 explicitly designates BP3 as not applicable and states that in-frame deletions/insertions in repetitive regions without known function are captured by bioinformatic tool prediction and domain analysis. NM_007294.4:c.1222A>G is a missense substitution, not an in-frame deletion or insertion, so the BP3 repeat-region criterion cannot apply.

VCEP rule
ENIGMA BRCA1/2 BP3: Do not use; the criterion is captured by bioinformatic tool prediction and domain analysis.
Evidence considered
  • The case annotation identifies NM_007294.4:c.1222A>G as a missense substitution rather than an in-frame insertion or deletion.
  • ENIGMA Specification v1.2 Table 1 states that BP3 is not applicable and that repeat-region in-frame indels are captured through bioinformatic and domain analysis.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
BP5 N/ANot applicable: combined clinical LR 1.8748372548618257 <= 0.48? no, placing it in ENIGMA's neutral BP5 interval. Details ▾Hide ▴
Reasoning

The exact BRCA1 c.1222A>G/p.(Lys408Glu)/K408E row reports a combined LR of 1.8748372548618257 and explicitly says the combined LR is not <0.5 or >2. The governing ENIGMA BP5 thresholds are LR <=0.48 for Supporting, <=0.23 for Moderate, <=0.05 for Strong, and <=0.00285 for Very Strong. The required operator is <=, and the decisive comparison is 1.8748372548618257 <= 0.48? no. Because the LR is >0.48 and <2.08, the ENIGMA neutral interval makes BP5 not applicable.

Rule
BP5 uses combined clinical LR: Supporting <=0.48:1; Moderate <=0.23:1; Strong <=0.05:1; Very Strong <=0.00285:1. The exact neutral result is not applicable.
Evidence considered
  • The exact clinical-history LR row reports combined LR 1.8748372548618257 and states: 'Combined LR is not <0.5 or >2'.
  • The ENIGMA BP5 rule requires LR <=0.48 for Supporting, <=0.23 for Moderate, <=0.05 for Strong, or <=0.00285 for Very Strong; combined LR >0.48 and <2.08 is not informative and BP5 is not applicable.
Still missing
  • No exact c.1222A>G, p.Lys408Glu, or p.K408E entry was found in Specifications_V1.2_2024-11-18.docx.txt; its BP5 rule was consulted.
Sources
vcep_pmid_31853058_brca1_clinical_history_lrvcep_humu_40_1557_s001cspec ↗PMID:31853058 ↗PMID:17924331 ↗
BP6 VCEPNot applicable: ClinVar has zero expert-panel submissions for the exact variant, so ordinary laboratory benign labels cannot trigger BP6. Details ▾Hide ▴
Reasoning

The exact ClinVar record for NM_007294.4:c.1222A>G (p.Lys408Glu) has no expert-panel submission and contains only ordinary laboratory submissions, including benign and likely-benign labels. The ENIGMA VCEP specification marks BP6 as not applicable for this VCEP. Under the required expert-panel-only rule, no BP6 evidence can be applied.

VCEP rule
Apply BP6 only for an exact-variant ClinVar expert-panel Benign or Likely benign classification; ordinary laboratory submissions and aggregate labels do not qualify.
Evidence considered
  • The exact ClinVar submission audit counts expert_panel_submissions as 0 and usable_for_classification as 0.
  • The ENIGMA VCEP rule states: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.'
Sources
clinvar ↗cspec ↗
BP7 N/ANot applicable: c.1222A>G is missense, producing p.Lys408Glu rather than a synonymous change. Details ▾Hide ▴
Reasoning

BP7 applies only to synonymous or qualifying intronic variants. NM_007294.4:c.1222A>G produces the missense substitution p.Lys408Glu (p.K408E), so BP7 is outside its criterion scope and is not evaluated.

Rule
BP7 is applicable only to synonymous or qualifying intronic variants; this missense variant is out of scope.
Evidence considered
  • The case normalization identifies NM_007294.4:c.1222A>G as missense, encoding NP_009225.1:p.(Lys408Glu), p.(K408E).
  • ENIGMA BRCA1 v1.2 limits BP7 to silent variants and qualifying intronic variants, including BP7 supporting only when the applicable benign splice-prediction condition is met.
Sources
cspec ↗

Identifiers

Gene
BRCA1
Transcript
NM_007294.4
Coding (HGVS c.)
NM_007294.4:c.1222A>G
Protein (HGVS p.)
NP_009225.1:p.(Lys408Glu)
GRCh38
chr17:43094309 T>C
GRCh37
chr17:41246326 T>C
Location and type
Exon 10 · missense
ClinVar
1786099, 1357359, 1349608, 954020, 951096, 928447, 824982, 818986, 661167, 187465
COSMIC
COSV99066385

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 41 / 1,614,214 alleles AF 2.54e-05 · 0 homozygotes · FAF 2.59e-05
gnomAD v2.1 1 / 250,812 alleles AF 3.99e-06 · 0 homozygotes
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 2.5e-05 · 41 / 1,614,214 alleles · 0 hom · FAF 2.6e-05
European (non-Finnish)41 / 1,180,030 3.5e-05
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.

gnomAD v2.1

AF 4e-06 · 1 / 250,812 alleles · 0 hom
European (non-Finnish)1 / 113,218 8.8e-06
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 2.53994e-05; MAF= 0.00254%, 41/1614214 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.47449e-05; MAF= 0.00347%, 41/1180030 alleles, homozygotes = 0); grpmax FAF= 2.585e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.98705e-06; MAF= 0.00040%, 1/250812 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.83252e-06; MAF= 0.00088%, 1/113218 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -229 bp
0.000
SpliceAI acceptor gainat +41 bp
0.000
SpliceAI donor lossat +435 bp
0.035
SpliceAI donor gainat -32 bp
0.001
Pangolin splice lossmagnitude shown
-0.009
Pangolin splice gain
0.009

Other predictors

REVEL
0.550
BayesDel
-0.103

How the predictions were used

PP3 Not met: missense REVEL 0.55 is below the ClinGen SVI supporting PP3 threshold of 0.644. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, so the missense protein-impact path applies and SpliceAI is not used for PP3/BP4. No governing ENIGMA row assigning PP3 was found for c.1222A>G, p.Lys408Glu, or p.K408E in the searched supplementary tables, specification document, appendices, or Houdayer full text. The case REVEL score is 0.55, below the published ClinGen SVI supporting PP3 threshold of 0.644 (Pejaver et al. 2022, PMID:36413997), so PP3 is not met. The ENIGMA BRCA1 specification also requires BayesDel no-AF >=0.28 for its missense protein-impact PP3 route and limits that route to a clinically important functional domain; p.Lys408Glu is outside the listed BRCA1 RING, coiled-coil, and BRCT domains, and the available BayesDel score is -0.10342.

Rule
Missense variant: use REVEL only for this group's computational protein-impact assessment; PP3 supporting requires REVEL >=0.644 under the published ClinGen SVI calibration. ENIGMA BRCA1 v1.2 additionally specifies BayesDel no-AF >=0.28 and a listed clinically important domain for its missense PP3 route.
Evidence considered
  • The case normalization identifies NM_007294.4:c.1222A>G as the missense variant NP_009225.1:p.(Lys408Glu), p.(K408E), so the missense REVEL path is applicable and BP7 is not.
  • The local REVEL lookup reports a score of 0.55 for this variant.
  • ClinGen SVI REVEL calibration defines supporting PP3 at REVEL >=0.644; Pejaver et al. 2022, PMID:36413997.
  • ENIGMA BRCA1 v1.2 specifies the missense protein-impact PP3 route using BayesDel no-AF >=0.28 within a clinically important functional domain; its listed BRCA1 domains are RING aa 2-101, coiled-coil aa 1391-1424, and BRCT aa 1650-1857, while p.Lys408Glu is outside these domains.
  • The available BayesDel no-AF score is -0.10342, below the ENIGMA PP3 threshold, and no governing VCEP PP3 lookup row was found for this variant after searching c.1222A>G, p.Lys408Glu, and p.K408E.
Still missing
  • No PP3, BP4, or BP7 assignment for c.1222A>G, p.Lys408Glu, or p.K408E was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No PP3, BP4, or BP7 assignment for c.1222A>G, p.Lys408Glu, or p.K408E was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No PP3, BP4, or BP7 assignment for c.1222A>G, p.Lys408Glu, or p.K408E was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No PP3, BP4, or BP7 assignment for c.1222A>G, p.Lys408Glu, or p.K408E was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗revel
BP4 Not met: missense REVEL 0.55 exceeds the ClinGen SVI supporting BP4 threshold of <=0.29. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, so the missense protein-impact path applies and SpliceAI is not used for BP4. No governing ENIGMA row assigning BP4 was found for c.1222A>G, p.Lys408Glu, or p.K408E in the searched supplementary tables, specification document, appendices, or Houdayer full text. The case REVEL score is 0.55, above the published ClinGen SVI supporting BP4 threshold of <=0.29 (Pejaver et al. 2022, PMID:36413997), placing it outside the benign-supporting range; the gray-zone result does not permit substitution of the SpliceAI score. The ENIGMA BRCA1 missense BP4 rule also requires no protein impact by BayesDel and no splice impact within a clinically important functional domain, whereas p.Lys408Glu is outside the listed domains and the BayesDel score is -0.10342.

Rule
Missense variant: use REVEL only for this group's computational protein-impact assessment; BP4 supporting requires REVEL <=0.29 under the published ClinGen SVI calibration. A gray-zone REVEL result does not permit substitution of SpliceAI.
Evidence considered
  • The case normalization identifies NM_007294.4:c.1222A>G as the missense variant NP_009225.1:p.(Lys408Glu), p.(K408E), so the missense REVEL path is applicable and SpliceAI is not used for BP4.
  • The local REVEL lookup reports a score of 0.55 for this variant.
  • ClinGen SVI REVEL calibration defines supporting BP4 at REVEL <=0.29; Pejaver et al. 2022, PMID:36413997.
  • ENIGMA BRCA1 v1.2 specifies the missense BP4 route with BayesDel no-AF <=0.15 and SpliceAI <=0.1 within a clinically important functional domain; its listed BRCA1 domains are RING aa 2-101, coiled-coil aa 1391-1424, and BRCT aa 1650-1857, while p.Lys408Glu is outside these domains.
  • The available BayesDel no-AF score is -0.10342, but the REVEL result is not within the calibrated BP4 range; the missense gray-zone result does not license using the available SpliceAI max delta of 0.035 as BP4 support.
Still missing
  • No PP3, BP4, or BP7 assignment for c.1222A>G, p.Lys408Glu, or p.K408E was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No PP3, BP4, or BP7 assignment for c.1222A>G, p.Lys408Glu, or p.K408E was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No PP3, BP4, or BP7 assignment for c.1222A>G, p.Lys408Glu, or p.K408E was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No PP3, BP4, or BP7 assignment for c.1222A>G, p.Lys408Glu, or p.K408E was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗revel
BP7 N/ANot applicable: c.1222A>G is missense, producing p.Lys408Glu rather than a synonymous change. Details ▾Hide ▴
Reasoning

BP7 applies only to synonymous or qualifying intronic variants. NM_007294.4:c.1222A>G produces the missense substitution p.Lys408Glu (p.K408E), so BP7 is outside its criterion scope and is not evaluated.

Rule
BP7 is applicable only to synonymous or qualifying intronic variants; this missense variant is out of scope.
Evidence considered
  • The case normalization identifies NM_007294.4:c.1222A>G as missense, encoding NP_009225.1:p.(Lys408Glu), p.(K408E).
  • ENIGMA BRCA1 v1.2 limits BP7 to silent variants and qualifying intronic variants, including BP7 supporting only when the applicable benign splice-prediction condition is met.
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.55. BayesDel score = -0.10342.

9 paper records listed. 1 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.

Cited in the classification

  • Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots".
    Dines JN et al. · 2020 May
    The paper does not explicitly mention BRCA1 c.1222A>G or p.(K408E), but residue 408 lies within BRCA1 exon 11, which the authors classify as a missense coldspot. Exon 11 had no confirmed pathogenic or likely pathogenic missense variants, 69 benign or likely benign variants, and 1048 VUS; the estimated odds ratio for pathogenicity was <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, paragraph beginning ‘By contrast, exon 11 accounts for ~60% of the coding sequence’; Table 1; Table 2

    Context Curated ClinVar missense-variant data for BRCA1 transcript NM_007294.3, queried October 2019; regional odds-of-pathogenicity analysis with Bayesian translation to ACMG/AMP categories.

Other recorded publications

  • Evolution of the tumor suppressor BRCA1 locus in primates: implications for cancer predisposition.
    No paper-specific finding is recorded.
    PMID 15385441 ↗
  • Missense variants of uncertain significance (VUS) altering the phosphorylation patterns of BRCA1 and BRCA2.
    No paper-specific finding is recorded.
    PMID 23704879 ↗
  • 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 ↗
  • Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
    Trepanier A et al. · 2004
    No paper-specific finding is recorded.
    PMID 15604628 ↗
  • The emerging landscape of breast cancer susceptibility.
    Stratton MR et al. · 2008
    No paper-specific finding is recorded.
    PMID 18163131 ↗
  • ACOG Practice Bulletin No. 103: Hereditary breast and ovarian cancer syndrome.
    No paper-specific finding is recorded.
    PMID 19305347 ↗
  • NSGC practice guideline: risk assessment and genetic counseling for hereditary breast and ovarian cancer.
    No paper-specific finding is recorded.
    PMID 23188549 ↗
  • 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 41 / 1,614,214 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.035 Open source ↗
ClinVar 5 Uncertain significance · 4 Likely benign · 2 Benign Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

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

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 2.53994e-05; MAF= 0.00254%, 41/1614214 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.47449e-05; MAF= 0.00347%, 41/1180030 alleles, homozygotes = 0); grpmax FAF= 2.585e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.98705e-06; MAF= 0.00040%, 1/250812 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.83252e-06; MAF= 0.00088%, 1/113218 alleles, homozygotes = 0).

gnomAD-Canada

Absent from 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 Benign (2 clinical laboratories). (ClinVarID = 37399)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.55. BayesDel score = -0.10342.

Functional

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

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV99066385, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.