0%
BRCA1c.2342A>CLikely benign
Print report
Variant interpretation report

BRCA1 c.2342A>C, p.(Glu781Ala)

NM_007294.4:c.2342A>C NP_009225.1:p.(Glu781Ala) Missense · exon 10 View identifiers
Classification
Likely benign

Variant description:

No variant summary was recorded for this case.

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

Likely benign.A likely 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: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PP4Supporting
PP4 · supporting

Met at Supporting: the exact-variant clinical-history likelihood ratio is 3.1586, satisfying the ENIGMA PP4 threshold 3.1586 >= 2.08.

Benign criteria applied · 1
BP1Strong
BP1 · strong

Met, strong: p.Glu781Ala is outside all ENIGMA domains and SpliceAI maximum delta 0.018 is below the <=0.1 threshold.

Recorded classification: Likely benign

Likely Benign: BP1 (strong) contributes -4 points and PP4 (supporting) contributes +1 under the ENIGMA conflicting-evidence point system, yielding -3.

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
13 / 1,613,960 alleles

gnomAD v4.1: 13 / 1,613,960 alleles. Recorded AF 8.05472e-06. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

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

Recorded REVEL score: 0.423. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied
ClinVar submissions
8 reported laboratory submissions

7 Uncertain significance · 1 Uncertain Significance. ClinVar API review status: criteria provided, conflicting classifications.

Context only ClinVar ↗
Functional evidence
Statement recorded

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

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

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

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

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

28 criteria with recorded statuses: 2 met · 6 not met · 8 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

For the requested consequence/LOF criteria, NM_007294.4:c.2342A>C is a missense substitution (p.Glu781Ala); ENIGMA BRCA1 VCEP v1.2 makes PVS1, PM4, and BP3 inapplicable to this consequence.

SpliceAI maximum delta 0.018 provides no indication that the exonic missense variant should be reinterpreted as a splice-site loss-of-function event.

Neither PS3 nor BS3 is assigned because the governing ENIGMA functional-assay sources contain no exact entry or variant-specific assay result for NM_007294.4:c.2342A>C (p.Glu781Ala/p.E781A).

The distinct c.5342A>C/p.Glu1781Ala Table 9 record was not used.

Among the requested criteria, PP4 Supporting is met from the exact Li et al. clinical-history LR of 3.158578379510139; PS4 is not assessed because required case-control statistics are unavailable; BP5 is not met because 3.158578379510139 <= 0.48 is false; PP5 and BP6 are not applicable because no exact-variant ClinVar Expert Panel classification exists.

PM3 is not assessed because the VCEP-required Fanconi Anemia phenotype, co-occurrent pathogenic or likely pathogenic BRCA1 variant, and phase evidence are not documented.

BP2 is not applicable because the governing ENIGMA BRCA1/2 VCEP specification explicitly excludes BP2 and limits it to BS2.

For this missense variant, the required single computational path is REVEL: score 0.423 is below supporting PP3 (>=0.644) and above supporting BP4 (<=0.29), so neither PP3 nor BP4 is met; BP7 is not applicable.

Met · 2

PP4 SupportingMet at Supporting: the exact-variant clinical-history likelihood ratio is 3.1586, satisfying the ENIGMA PP4 threshold 3.1586 >= 2.08. Details ▾Hide ▴
Reasoning

ENIGMA restricts PP4 to clinically calibrated multifactorial likelihood evidence. The exact BRCA1/c.2342A>C row in the Li et al. 2020 clinical-history LR table reports LOG(LR)=1.150122046470642, N_Probands=1, and LR=3.158578379510139. The governing PP4 operator is >=, and the explicit comparison is 3.158578379510139 >= 2.08? yes; therefore PP4 Supporting is met. The VCEP threshold for PP4 Moderate is >=4.3, so no higher strength is assigned. This is a clinical-history LR component only and is not being used as PS4, PP1, segregation, pathology, or co-occurrence evidence.

Rule
ENIGMA PP4 uses combined multifactorial clinical LR: Supporting >=2.08:1, Moderate >=4.3:1, Strong >=18.7:1, Very Strong >=350:1.
Evidence considered
  • The exact BRCA1 c.2342A>C row reports LOG(LR)=1.150122046470642, N_Probands=1, and LR=3.158578379510139.
  • The governing ENIGMA PP4 operator is >=; explicit inequality: 3.158578379510139 >= 2.08? yes.
  • ENIGMA PP4 thresholds are Supporting >=2.08, Moderate >=4.3, Strong >=18.7, and Very Strong >=350; 3.158578379510139 reaches Supporting only.
  • Li et al. describe multiplying per-variant likelihood ratios from probands carrying that variant to obtain a per-variant LR in a large multigene-panel clinical-history model.
Sources
cspec ↗PMID:31853058 ↗
BP1 StrongMet, strong: p.Glu781Ala is outside all ENIGMA domains and SpliceAI maximum delta 0.018 is below the <=0.1 threshold. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 BP1 rule applies BP1_Strong to missense variants outside a potentially clinically important functional domain when no splicing is predicted (SpliceAI <=0.1). p.Glu781Ala is outside the complete ENIGMA domain list: RING aa 2-101, coiled-coil aa 1391-1424, and BRCT aa 1650-1857. SpliceAI maximum delta is 0.018, which is below the governing 0.1 threshold. Therefore BP1_Strong is met. The exon 11 coldspot analysis is concordant but is not needed to meet the governing rule.

Rule
Apply BP1_Strong for a missense variant outside an ENIGMA clinically important functional domain when SpliceAI is <=0.1.
Evidence considered
  • ENIGMA BP1_Strong applies to missense variants outside a potentially clinically important domain with no predicted splicing impact, defined as SpliceAI <=0.1.
  • Residue 781 is outside the ENIGMA BRCA1 domains RING aa 2-101, coiled-coil aa 1391-1424, and BRCT aa 1650-1857.
  • SpliceAI maximum delta is 0.018, satisfying the governing <=0.1 no-splicing threshold.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18spliceai ↗

Not met · 6 · evaluated, threshold not reached

PS1 Not met: no governing-VCEP pathogenic comparator for p.Glu781Ala/p.E781A was found, despite SpliceAI maximum delta 0.018 being below 0.1. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 specification permits PS1 for a missense variant only when it produces the same amino-acid substitution as a previously established pathogenic or likely pathogenic variant through a different nucleotide change, with no confirmed or predicted splicing effect. The governing VCEP files were searched for c.2342A>C, p.Glu781Ala, and p.E781A; no matching same-amino-acid pathogenic comparator was found. The variant has no significant predicted splicing impact (SpliceAI maximum delta 0.018), but that prerequisite alone does not establish PS1.

Rule
ENIGMA BRCA1 PS1 requires the same missense substitution as a VCEP-classified pathogenic or likely pathogenic variant caused by a different nucleotide change; both variants must lack confirmed or predicted splicing impact.
Evidence considered
  • ENIGMA specifies PS1 for the same missense substitution as a previously established pathogenic variant caused by a different nucleotide change; the reference variant must be classified using the VCEP specification.
  • The governing VCEP files were searched under c.2342A>C, p.Glu781Ala, and p.E781A without finding a same-amino-acid pathogenic comparator.
  • SpliceAI maximum delta is 0.018, below the ENIGMA no-predicted-splicing threshold of 0.1, but this only satisfies the splicing prerequisite and does not supply the required pathogenic comparator.
Still missing
  • No exact variant or same-amino-acid pathogenic comparator entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact variant or same-amino-acid pathogenic comparator entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact variant entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No exact variant entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • No exact variant entry was found in Specifications_Table9_V1.2_2024-11-18.xlsx.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18spliceai ↗
PP3 Not met: missense REVEL score 0.423 is below the >=0.644 supporting PP3 threshold. Details ▾Hide ▴
Reasoning

NM_007294.4:c.2342A>C is a missense variant encoding p.(Glu781Ala), so this group's applicable computational path is REVEL only; SpliceAI is not used for missense PP3/BP4 assessment. The REVEL score is 0.423, below the generic ClinGen SVI supporting PP3 threshold of >=0.644 from Pejaver et al. 2022 (PMID:36413997), and therefore PP3 is not met. No exact entry for c.2342A>C, p.Glu781Ala, or p.E781A was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.

Rule
For a missense variant, evaluate PP3 using REVEL only; supporting PP3 requires REVEL >=0.644 under the supplied ClinGen SVI calibration.
Evidence considered
  • The case normalization identifies NM_007294.4:c.2342A>C as the missense substitution NP_009225.1:p.(Glu781Ala), so REVEL is the applicable computational path and SpliceAI is not used for PP3.
  • The local REVEL result is 0.423; the supplied ClinGen SVI calibration assigns supporting PP3 at REVEL >=0.644 (Pejaver et al. 2022, PMID:36413997), so the score does not meet PP3.
  • The ENIGMA BRCA1/2 VCEP v1.2 specification governs PP3/BP4/BP7; the requested variant notations were searched in all four declared full-text VCEP files and no exact entry was found.
Still missing
  • No exact c.2342A>C, p.Glu781Ala, or p.E781A entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No exact c.2342A>C, p.Glu781Ala, or p.E781A entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.2342A>C, p.Glu781Ala, or p.E781A entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.2342A>C, p.Glu781Ala, or p.E781A entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗revelvcep_supplementarytables_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18
BA1 Not met: the variant is absent from governing gnomAD v2.1/v3.1 non-cancer datasets, so no filter allele frequency exceeds the ENIGMA BA1 threshold of 0.001. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP BA1 rule requires filter allele frequency above 0.001 (0.1%) in a non-founder population from gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes, with adequate read depth and passing quality control. The variant is absent from both governing non-cancer datasets, so no qualifying FAF exceeds 0.001. gnomAD v4.1 all-comers reports grpmax FAF 5.42e-06 and is not substituted for the explicitly specified older non-cancer datasets.

Rule
Filter allele frequency (FAF) is above 0.1% (FAF > 0.001) in gnomAD v2.1 non-cancer exome-only and/or gnomAD v3.1 non-cancer genome non-founder populations; do not apply if read depth <20 or quality control fails.
Evidence considered
  • ENIGMA BRCA1 v1.2 specifies BA1 when maximum non-founder filter allele frequency is above 0.001 (0.1%) in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes; it separately requires read depth at least 20 and quality-control eligibility.
  • The case evidence reports the variant absent from gnomAD v2.1 non-cancer and absent from gnomAD v3.1 non-cancer, so the governing BA1 frequency threshold is not reached.
  • For context only, gnomAD v4.1 all-comers reports 13/1,613,960 total alleles, total AF 8.05472e-06, and grpmax FAF 5.42e-06; the VCEP's specified non-cancer v2.1/v3.1 sources take precedence over this newer all-comers dataset.
Still missing
  • No c.2342A>C, p.Glu781Ala, or p.E781A entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No c.2342A>C, p.Glu781Ala, or p.E781A entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No c.2342A>C, p.Glu781Ala, or p.E781A entry was found in Appendices_V1.2_2024-11-18.docx.txt.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗vcep_supplementarytables_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18
BS1 Not met: the variant is absent from governing gnomAD v2.1/v3.1 non-cancer datasets, and the available gnomAD v4.1 grpmax FAF is 5.42e-06 below 0.00002. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP BS1 rule requires maximum non-founder filter allele frequency above 0.0001 for BS1 Strong, or above 0.00002 and at most 0.0001 for BS1 Supporting, in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes. The variant is absent from both governing non-cancer datasets, so neither BS1 threshold is met. The gnomAD v4.1 all-comers grpmax FAF of 5.42e-06 is also below 0.00002 and cannot replace the specified non-cancer sources.

Rule
BS1 Strong applies above 0.0001; BS1 Supporting applies above 0.00002 and at most 0.0001, using maximum non-founder filter allele frequency in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes; do not apply if read depth <20 or quality control fails.
Evidence considered
  • ENIGMA BRCA1 v1.2 specifies BS1 Strong above 0.0001 and BS1 Supporting above 0.00002 through 0.0001, using maximum non-founder filter allele frequency in gnomAD v2.1 non-cancer exomes and/or gnomAD v3.1 non-cancer genomes; read depth must be at least 20 and quality control must pass.
  • The case evidence reports absence from both gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer, so no governing dataset provides a frequency in either BS1 range.
  • The available gnomAD v4.1 all-comers result has grpmax FAF 5.42e-06, below the 0.00002 BS1 Supporting lower bound, and is not used to override the VCEP source specification.
Still missing
  • No c.2342A>C, p.Glu781Ala, or p.E781A entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No c.2342A>C, p.Glu781Ala, or p.E781A entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No c.2342A>C, p.Glu781Ala, or p.E781A entry was found in Appendices_V1.2_2024-11-18.docx.txt.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗vcep_supplementarytables_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18
BP4 Not met: missense REVEL score 0.423 exceeds the <=0.29 supporting BP4 threshold and is therefore gray-zone. Details ▾Hide ▴
Reasoning

NM_007294.4:c.2342A>C is a missense variant encoding p.(Glu781Ala), so this group's applicable computational path is REVEL only; SpliceAI is not used for missense PP3/BP4 assessment. The REVEL score is 0.423, above the generic ClinGen SVI supporting BP4 threshold of <=0.29 from Pejaver et al. 2022 (PMID:36413997), placing it in the gray zone; BP4 is not met and the available SpliceAI score cannot substitute. No exact entry for c.2342A>C, p.Glu781Ala, or p.E781A was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.

Rule
For a missense variant, evaluate BP4 using REVEL only; supporting BP4 requires REVEL <=0.29 under the supplied ClinGen SVI calibration, and a gray-zone result does not permit substitution of SpliceAI.
Evidence considered
  • The case normalization identifies NM_007294.4:c.2342A>C as the missense substitution NP_009225.1:p.(Glu781Ala), so REVEL is the applicable computational path and SpliceAI is not used for BP4.
  • The local REVEL result is 0.423; the supplied ClinGen SVI calibration assigns supporting BP4 at REVEL <=0.29 (Pejaver et al. 2022, PMID:36413997), so the score is gray-zone and does not meet BP4.
  • The ENIGMA BRCA1/2 VCEP v1.2 specification governs PP3/BP4/BP7; the requested variant notations were searched in all four declared full-text VCEP files and no exact entry was found.
Still missing
  • No exact c.2342A>C, p.Glu781Ala, or p.E781A entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No exact c.2342A>C, p.Glu781Ala, or p.E781A entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.2342A>C, p.Glu781Ala, or p.E781A entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.2342A>C, p.Glu781Ala, or p.E781A entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗revelvcep_supplementarytables_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18
BP5 Not met: the exact-variant clinical-history LR is 3.1586, failing the ENIGMA BP5 comparison 3.1586 <= 0.48. Details ▾Hide ▴
Reasoning

ENIGMA restricts BP5 to clinically calibrated multifactorial likelihood evidence against pathogenicity. The exact Li et al. row reports LR=3.158578379510139. For BP5 Supporting, the governing operator is <= with threshold 0.48, and the explicit comparison is 3.158578379510139 <= 0.48? no. The LR is instead above the benign-evidence range and is in the PP4-supporting range, so BP5 is not met. No BP5 strength is assigned.

Rule
ENIGMA BP5 uses combined multifactorial clinical LR against pathogenicity: Supporting <=0.48:1, Moderate <=0.23:1, Strong <=0.05:1, Very Strong <=0.00285:1.
Evidence considered
  • The exact BRCA1 c.2342A>C row reports LR=3.158578379510139.
  • The governing BP5 Supporting operator is <=; explicit inequality: 3.158578379510139 <= 0.48? no.
  • ENIGMA BP5 thresholds are Supporting <=0.48, Moderate <=0.23, Strong <=0.05, and Very Strong <=0.00285; the observed LR meets none of them.
  • The VCEP neutral zone is >0.48 to <1.00 for BP5, while this LR is above 1.00 and therefore is not benign-direction evidence.
Sources
cspec ↗PMID:31853058 ↗

Not assessed · 8 · no assessment recorded

PS3 Not assessed: no exact variant-specific functional assay entry or calibrated damaging result was found for c.2342A>C/p.Glu781Ala. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 specification requires well-established functional studies showing a damaging protein effect, with assay-specific PS3 strength recommendations in Table 9. Exact searches for NM_007294.4:c.2342A>C, p.Glu781Ala, and p.E781A found no variant-specific entry in Specifications_Table9_V1.2_2024-11-18.xlsx.txt, SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or HUMU-40-1557-s001.xlsx.txt. The Table 9 row for c.5342A>C/p.Glu1781Ala is a different variant and cannot support PS3 for c.2342A>C. No already-extracted case paper finding provides variant-specific functional assay evidence. Therefore PS3 cannot be assigned.

Rule
Apply PS3 only for well-established in vitro or in vivo functional studies supportive of a damaging effect measured through protein function or combined mRNA and protein data; use the ENIGMA Table 9 calibrated assignment when an exact variant entry exists.
Evidence considered
  • ENIGMA Table 1 defines PS3 for functional assays measuring protein function, or mRNA and protein together, and directs variant-specific calibrated assignments to Table 9.
  • Exact searches of all five governing VCEP text conversions found no entry for c.2342A>C, p.Glu781Ala, or p.E781A.
  • The Table 9 entry c.5342A>C/p.Glu1781Ala is a distinct variant and was excluded from consideration.
  • The available paper extraction set contains no variant-specific functional assay finding for c.2342A>C/p.E781A.
Still missing
  • No exact c.2342A>C, p.Glu781Ala, or p.E781A entry in Specifications_Table9_V1.2_2024-11-18.xlsx.txt.
  • No exact c.2342A>C, p.Glu781Ala, or p.E781A entry in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No exact c.2342A>C, p.Glu781Ala, or p.E781A entry in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.2342A>C, p.Glu781Ala, or p.E781A entry in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.2342A>C, p.Glu781Ala, or p.E781A entry in HUMU-40-1557-s001.xlsx.txt.
  • No variant-specific functional paper finding was available in paper_extracts.json for this criterion.
Sources
vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_humu_40_1557_s001
PS4 Not assessed: no variant-specific case-control p-value, odds ratio, or confidence interval is available to apply the ENIGMA PS4 requirements. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 specification requires case-control evidence for PS4 with p-value <=0.05, OR >=4, and a lower confidence interval excluding 2.0. The available case evidence contains no variant-specific affected-versus-control counts, odds ratio, p-value, or confidence interval for NM_007294.4:c.2342A>C (p.Glu781Ala/p.E781A). The Li et al. clinical-history record contains one proband and an LR, but the VCEP expressly restricts that evidence to PP4/BP5 and it cannot establish PS4. No exact variant entry was found when Specifications_V1.2_2024-11-18.docx was searched for c.2342A>C, p.Glu781Ala, and p.E781A.

Rule
ENIGMA PS4: case-control p-value <=0.05, OR >=4, and lower confidence interval excludes 2.0.
Evidence considered
  • ENIGMA specifies PS4 only for case-control studies with p-value <=0.05, OR >=4, and a lower confidence interval excluding 2.0.
  • The case materials provide no variant-specific case-control counts or PS4 statistics for NM_007294.4:c.2342A>C.
  • The exact Li clinical-history row has N_Probands=1 and is restricted by the VCEP materials to PP4/BP5, not PS4.
Still missing
  • No exact variant entry found in Specifications_V1.2_2024-11-18.docx for c.2342A>C, p.Glu781Ala, or p.E781A; the file supplies the PS4 rule but not case-level results.
  • Variant-specific affected-case and control counts, p-value, odds ratio, and confidence interval are unavailable.
Sources
cspec ↗
PM2 Not assessed: the variant is absent from governing gnomAD non-cancer datasets, but the required regional average read depth of at least 25 is undocumented. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP PM2 rule is PM2 Supporting for absence from controls in an outbred population using gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, provided the surrounding region has average read depth at least 25; a single observation is not informative. The variant is reported absent from both governing non-cancer datasets, but the case evidence does not provide the required regional read-depth value or quality-control/depth confirmation. Therefore PM2 cannot be assigned from the available evidence, despite the absence result.

Rule
PM2 Supporting applies when absent from controls in an outbred population in gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, with average read depth at least 25 around the variant; do not apply for a single observation or failed quality control.
Evidence considered
  • ENIGMA BRCA1 v1.2 specifies PM2 Supporting for absence from gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes, with regional average read depth at least 25; a one-time observation is not informative.
  • The case evidence reports the variant absent from gnomAD v2.1 non-cancer and absent from gnomAD v3.1 non-cancer.
  • No regional average read-depth value or explicit depth quality-control confirmation is present in the available population evidence, so the VCEP PM2 prerequisite cannot be verified.
Still missing
  • Regional average read depth for the variant is not provided; ENIGMA requires at least 25 for PM2.
  • Quality-control filter status for the absent non-cancer records is not independently documented.
  • No c.2342A>C, p.Glu781Ala, or p.E781A entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No c.2342A>C, p.Glu781Ala, or p.E781A entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No c.2342A>C, p.Glu781Ala, or p.E781A entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No c.2342A>C, p.Glu781Ala, or p.E781A entry was found in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗gnomad_v2 ↗vcep_supplementarytables_v1_2_2024_11_18vcep_humu_40_1557_s001vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18
PM3 Not assessed: no Fanconi Anemia phenotype, co-occurrent pathogenic BRCA1 variant, or phase evidence is documented for this variant, so the VCEP PM3 point thresholds cannot be reached. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 VCEP specification restricts PM3 to a BRCA1-related Fanconi Anemia phenotype with a co-occurrent pathogenic or likely pathogenic BRCA1 variant, scored by Table 6: one point for phase-unknown co-occurrence, two points for a confirmed or inferable in-trans pathogenic/likely pathogenic variant, and PM3_Supporting/PM3/PM3_Strong at totals of 1/2/4 or more points. The consolidated case-evidence bundle and vcep_materials.json provide no affected-proband Fanconi Anemia phenotype, no co-occurrent pathogenic or likely pathogenic BRCA1 variant, and no phase or trans evidence for NM_007294.4:c.2342A>C (p.Glu781Ala; p.E781A). Therefore PM3 cannot be assigned from the available evidence.

Rule
Apply PM3 only for a patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia and co-occurrent variants in the same gene; assign PM3_Supporting at 1 point, PM3 at 2 points, and PM3_Strong at 4 or more points.
Evidence considered
  • ENIGMA BRCA1/2 VCEP Specifications V1.2 Table 1 states that PM3 applies to a patient with a BRCA1- or BRCA2-related Fanconi Anemia phenotype and co-occurrent variants in the same gene.
  • ENIGMA BRCA1/2 VCEP Specifications V1.2 Table 6 assigns 1 point for phase-unknown co-occurrence, 2 points for a pathogenic or likely pathogenic variant in trans or homozygosity, and final PM3_Supporting, PM3, or PM3_Strong at totals of 1, 2, or at least 4 points, respectively.
  • The consolidated case-evidence bundle and vcep_materials.json contain no affected-proband Fanconi Anemia phenotype, co-occurrent pathogenic or likely pathogenic BRCA1 variant, or phase/trans observation for NM_007294.4:c.2342A>C (p.Glu781Ala; p.E781A).
Still missing
  • No affected-proband Fanconi Anemia phenotype or chromosome-breakage result is documented in the consolidated case-evidence bundle or vcep_materials.json.
  • No co-occurrent pathogenic or likely pathogenic BRCA1 variant and no phase/trans evidence are documented in the consolidated case-evidence bundle or vcep_materials.json.
  • No entry for c.2342A>C, p.Glu781Ala, or p.E781A was found in Specifications_V1.2_2024-11-18.docx.txt; the governing document therefore supplies the PM3 rule but no variant-specific PM3 assignment.
Sources
cspec ↗
PP1 Not assessed: no quantitative family co-segregation LR is available, and the separate clinical-history LR 3.158578379510139 is not segregation evidence. Details ▾Hide ▴
Reasoning

The governing ENIGMA specification requires quantitative co-segregation analysis with affected family members and assigns PP1 Supporting at LR ≥2.08, Moderate at LR ≥4.3, Strong at LR ≥18.7, and Very Strong at LR ≥350. The case evidence contains no proband-level pedigree, affected-relative genotypes and phenotypes, tested meioses, or quantitative co-segregation LR for NM_007294.4:c.2342A>C (p.Glu781Ala/p.E781A). The searched HUMU-40-1557-s001 VCEP spreadsheet contains no entry for c.2342A>C, p.Glu781Ala, or p.E781A. A separate clinical-history LR table has one c.2342A>C row with LR 3.158578379510139 and N_Probands 1, but that is not a segregation analysis and its index guidance restricts it to PP4/BP5, so it cannot establish PP1.

Rule
PP1 is assigned only from quantitative co-segregation with affected family members; LR ≥2.08 supporting, ≥4.3 moderate, ≥18.7 strong, or ≥350 very strong.
Evidence considered
  • ENIGMA v1.2 Appendix I/Table 1 requires quantitative co-segregation analysis and sets PP1 thresholds of LR ≥2.08 supporting, ≥4.3 moderate, ≥18.7 strong, and ≥350 very strong.
  • HUMU-40-1557-s001.xlsx.txt was searched for c.2342A>C, p.Glu781Ala, and p.E781A; no matching row was found.
  • The separate PMID:31853058 clinical-history table contains BRCA1 c.2342A>C with N_Probands 1 and LR 3.158578379510139, but the source guidance restricts that table to PP4/BP5 and it does not provide segregation data.
Still missing
  • No proband-level pedigree with affected-relative genotypes, phenotypes, tested meioses, or a quantitative co-segregation LR was provided.
  • No entry for c.2342A>C, p.Glu781Ala, or p.E781A was found in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗vcep_humu_40_1557_s001vcep_pmid_31853058_brca1_clinical_history_lr
BS2 Not assessed: gnomAD reports zero homozygotes, but ENIGMA BS2 requires phenotyped clinical-cohort observations with phase and age or follow-up information. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 VCEP repurposes BS2 for phenotyped clinical or research-cohort observations of the variant in trans with a pathogenic or likely pathogenic BRCA1 variant, or as a homozygote, in an individual unlikely to have Fanconi Anemia. Points depend on age at cancer diagnosis or unaffected follow-up: for a homozygote, 2 points require age above 50 years or unaffected follow-up above 50 years, and 1 point requires age 40–50 years or equivalent follow-up; final BS2 strength requires at least 4 points, moderate 2 points, or supporting 1 point. Population frequency data are explicitly excluded from this calculation, and the case bundle provides no qualifying phenotyped individual, phase, age, or Fanconi Anemia assessment. gnomAD reports zero homozygotes, which does not establish BS2.

Rule
Apply BS2 only from phenotyped clinical or research-cohort observations of a variant in trans with a BRCA1 pathogenic/likely pathogenic variant or as a homozygote, absent Fanconi Anemia features; assign points by age/follow-up and sum points for BS2 strength.
Evidence considered
  • ENIGMA BRCA1 v1.2 assigns BS2 points only to phenotyped individuals from clinical or research cohorts with a homozygous or appropriately phased co-occurring pathogenic/likely pathogenic observation and an unlikely Fanconi Anemia phenotype.
  • The ENIGMA table assigns homozygote observations 2 points when cancer-free follow-up or first cancer onset is above 50 years, and 1 point when the corresponding age is 40–50 years; final BS2 requires at least 4 points, moderate 2 points, or supporting 1 point.
  • The case evidence reports zero homozygotes in gnomAD v4.1; the VCEP explicitly states that frequency-based observations are not to be used for BS2, so this does not establish the criterion.
Still missing
  • No qualifying phenotyped clinical or research-cohort observation of this variant in trans with a BRCA1 pathogenic/likely pathogenic variant or as a homozygote was provided.
  • No phase information, age at cancer diagnosis, unaffected follow-up age, or Fanconi Anemia phenotype assessment was provided.
  • No c.2342A>C, p.Glu781Ala, or p.E781A entry was found in HUMU-40-1557-s001.xlsx.txt.
  • No c.2342A>C, p.Glu781Ala, or p.E781A entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No c.2342A>C, p.Glu781Ala, or p.E781A entry was found in Appendices_V1.2_2024-11-18.docx.txt.
Sources
cspec ↗gnomad_v4 ↗vcep_humu_40_1557_s001vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18
BS3 Not assessed: no exact variant-specific functional assay entry or calibrated benign result was found for c.2342A>C/p.Glu781Ala. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 specification requires well-established functional studies showing no damaging protein effect, with assay-specific BS3 strength recommendations in Table 9. Exact searches for NM_007294.4:c.2342A>C, p.Glu781Ala, and p.E781A found no variant-specific entry in Specifications_Table9_V1.2_2024-11-18.xlsx.txt, SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or HUMU-40-1557-s001.xlsx.txt. The Table 9 row for c.5342A>C/p.Glu1781Ala is a different variant and cannot support BS3 for c.2342A>C. No already-extracted case paper finding provides variant-specific benign functional assay evidence. Therefore BS3 cannot be assigned.

Rule
Apply BS3 only for well-established in vitro or in vivo functional studies showing no damaging effect measured through protein function or combined mRNA and protein data; use the ENIGMA Table 9 calibrated assignment when an exact variant entry exists.
Evidence considered
  • ENIGMA Table 1 defines BS3 for functional assays showing no damaging protein effect, or mRNA and protein together, and directs variant-specific calibrated assignments to Table 9.
  • Exact searches of all five governing VCEP text conversions found no entry for c.2342A>C, p.Glu781Ala, or p.E781A.
  • The Table 9 entry c.5342A>C/p.Glu1781Ala is a distinct variant and was excluded from consideration.
  • The available paper extraction set contains no variant-specific functional assay finding for c.2342A>C/p.E781A.
Still missing
  • No exact c.2342A>C, p.Glu781Ala, or p.E781A entry in Specifications_Table9_V1.2_2024-11-18.xlsx.txt.
  • No exact c.2342A>C, p.Glu781Ala, or p.E781A entry in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No exact c.2342A>C, p.Glu781Ala, or p.E781A entry in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.2342A>C, p.Glu781Ala, or p.E781A entry in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.2342A>C, p.Glu781Ala, or p.E781A entry in HUMU-40-1557-s001.xlsx.txt.
  • No variant-specific functional paper finding was available in paper_extracts.json for this criterion.
Sources
vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18vcep_humu_40_1557_s001
BS4 Not assessed: no affected-family non-segregation LR is available, while the reported clinical-history LR 3.158578379510139 is not BS4 evidence. Details ▾Hide ▴
Reasoning

The governing ENIGMA specification requires quantitative co-segregation analysis demonstrating lack of segregation in affected family members and assigns BS4 Supporting at LR ≤0.48, Moderate at LR ≤0.23, Strong at LR ≤0.05, and Very Strong at LR ≤0.00285. The case evidence contains no affected-family-member genotypes, phenotypes, tested meioses, or quantitative non-segregation LR for NM_007294.4:c.2342A>C (p.Glu781Ala/p.E781A). The searched HUMU-40-1557-s001 VCEP spreadsheet contains no entry for c.2342A>C, p.Glu781Ala, or p.E781A. The separate clinical-history LR table reports LR 3.158578379510139 for one proband, which is not a non-segregation analysis and is not evidence for BS4.

Rule
BS4 is assigned only from quantitative lack of segregation in affected family members; LR ≤0.48 supporting, ≤0.23 moderate, ≤0.05 strong, or ≤0.00285 very strong.
Evidence considered
  • ENIGMA v1.2 Appendix I/Table 1 requires quantitative analysis of lack of segregation in affected family members and sets BS4 thresholds of LR ≤0.48 supporting, ≤0.23 moderate, ≤0.05 strong, and ≤0.00285 very strong.
  • HUMU-40-1557-s001.xlsx.txt was searched for c.2342A>C, p.Glu781Ala, and p.E781A; no matching row was found.
  • The separate PMID:31853058 clinical-history table contains BRCA1 c.2342A>C with LR 3.158578379510139 and N_Probands 1, but this is not a quantitative non-segregation analysis and cannot establish BS4.
Still missing
  • No affected-family-member genotypes, phenotypes, tested meioses, or quantitative non-segregation LR was provided.
  • No entry for c.2342A>C, p.Glu781Ala, or p.E781A was found in HUMU-40-1557-s001.xlsx.txt.
Sources
cspec ↗vcep_humu_40_1557_s001vcep_pmid_31853058_brca1_clinical_history_lr
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: c.2342A>C is a missense substitution with SpliceAI maximum delta 0.018, not a null or canonical splice-site variant. Details ▾Hide ▴
Reasoning

NM_007294.4:c.2342A>C (NP_009225.1:p.(Glu781Ala), p.E781A) is a missense substitution. It does not create a premature termination codon, frameshift, canonical splice-site alteration, initiation-codon change, or exon-level deletion. The ENIGMA BRCA1 VCEP PVS1 framework applies to null variants and therefore does not apply to this missense consequence; the governing Table 4 is an exon-level null/splice-site decision table and contains no entry for this variant under c.2342A>C, p.Glu781Ala, or p.E781A. The variant has SpliceAI maximum delta 0.018, supporting its classification as non-splice-altering, but no PVS1 strength is assigned.

Rule
ENIGMA BRCA1 VCEP v1.2 PVS1 applies to null variants; a missense substitution is outside scope.
Evidence considered
  • The case annotation identifies NM_007294.4:c.2342A>C as NP_009225.1:p.(Glu781Ala), p.E781A, a missense substitution.
  • The ENIGMA BRCA1 specification defines PVS1 for null variants, including nonsense, frameshift, canonical splice-site, initiation-codon, and exon-deletion variants, with variable strength determined by its PVS1 decision tree.
  • SpliceAI reports a maximum delta score of 0.018, with no significant predicted splice impact.
  • The searched ENIGMA Table 4, full specification, appendices, and Houdayer paper contained no variant-specific entry for c.2342A>C, p.Glu781Ala, or p.E781A.
Still missing
  • No c.2342A>C, p.Glu781Ala, or p.E781A entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • No c.2342A>C, p.Glu781Ala, or p.E781A entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No c.2342A>C, p.Glu781Ala, or p.E781A entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No c.2342A>C, p.Glu781Ala, or p.E781A entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_table4_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18spliceai ↗
PS2 VCEPNot applicable: ENIGMA explicitly prohibits PS2 because de novo occurrences are not calibrated for BRCA1/2-related cancers. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 VCEP specification explicitly states that PS2 is not to be used for BRCA1/2-related cancers because these cancers occur relatively commonly and there is no information to calibrate the predictive capacity of de novo occurrences. No de novo evidence can therefore be assigned under this governing framework.

VCEP rule
Do not use PS2 for BRCA1/2-related cancers; no calibration exists for de novo occurrences.
Evidence considered
  • ENIGMA BRCA1/2 VCEP Specification v1.2 Table 1 assigns PS2 as do not use and gives the reason that BRCA1/2-related cancers occur relatively commonly without calibrated de novo predictive capacity.
Sources
cspec ↗
PM1 VCEPNot applicable: p.Glu781 lies outside ENIGMA domains aa 2-101, 1391-1424, and 1650-1857, while exon 11 has pathogenicity odds ratio <0.01. Details ▾Hide ▴
Reasoning

The case vcep_materials.json domain_tables key is empty, so the governing ENIGMA domain tables were consulted directly. ENIGMA lists BRCA1 critical or potentially clinically important domains as RING aa 2-101, coiled-coil aa 1391-1424, and BRCT aa 1650-1857. Residue E781 lies in none of these domains. The ENIGMA specification marks PM1 as not applicable and directs missense location/prediction evidence to BP1, BP4, or PP3. Independently, Dines et al. identified BRCA1 exon 11, containing this residue, as a coldspot with no confirmed pathogenic or likely pathogenic missense variants and an estimated pathogenicity odds ratio below 0.01.

VCEP rule
ENIGMA PM1 is not applicable; for BRCA1 missense variants, domain and calibrated prediction evidence is evaluated under BP1, BP4, and PP3.
Evidence considered
  • ENIGMA defines the approved BRCA1 clinically important domains as RING aa 2-101, coiled-coil aa 1391-1424, and BRCT aa 1650-1857; residue 781 is outside every listed domain.
  • ENIGMA Table 16 marks PM1 as not applicable for BRCA1/2 and directs this missense evidence to BP1, BP4, and PP3 instead.
  • Dines et al. report that BRCA1 exon 11 has no confirmed pathogenic or likely pathogenic missense variants and an estimated pathogenicity odds ratio of <0.01 (95% CI 0.0-0.01), classifying the region as a coldspot.
Still missing
  • vcep_materials.json contains an empty domain_tables object; domain assessment therefore used the complete domain definitions in the governing ENIGMA specification and appendices.
  • No exact variant or approved hotspot entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact variant or approved domain-residue entry was found in Appendices_V1.2_2024-11-18.docx.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18PMID:31911673 ↗
PM4 VCEPNot applicable: p.Glu781Ala changes one amino acid without altering protein length, whereas ENIGMA PM4 covers in-frame length changes or stop-loss variants. Details ▾Hide ▴
Reasoning

NM_007294.4:c.2342A>C causes the single amino-acid substitution p.Glu781Ala and produces no protein length change. The ENIGMA BRCA1 VCEP specification explicitly states that PM4 is not used and that the criterion is captured through the specified bioinformatic analysis; this missense substitution is neither an in-frame insertion/deletion nor a stop-loss variant. The governing ENIGMA files contain no entry for c.2342A>C, p.Glu781Ala, or p.E781A.

VCEP rule
ENIGMA BRCA1 VCEP v1.2: PM4 do not use; missense substitutions do not produce a protein length change.
Evidence considered
  • The case annotation identifies p.Glu781Ala as a missense substitution, so the encoded protein is shortened or lengthened by zero amino acids.
  • The ENIGMA BRCA1 specification states that PM4 is not used and defines its underlying concept as protein length changes from in-frame insertions/deletions or stop-loss variants.
  • The searched ENIGMA Table 4, full specification, appendices, and Houdayer paper contained no variant-specific entry for c.2342A>C, p.Glu781Ala, or p.E781A.
Still missing
  • No c.2342A>C, p.Glu781Ala, or p.E781A entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • No c.2342A>C, p.Glu781Ala, or p.E781A entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No c.2342A>C, p.Glu781Ala, or p.E781A entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No c.2342A>C, p.Glu781Ala, or p.E781A entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PM5 N/ANot applicable: c.2342A>C is missense p.Glu781Ala, whereas ENIGMA PM5 is reserved for PTC variants annotated with PVS1. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1 specification explicitly does not use classic missense PM5 and instead considers that evidence within the bioinformatic framework. Its repurposed PM5_VariableWeight (PTC) applies only to protein-termination-codon variants in an exon with a different proven pathogenic PTC variant, to add weight to a PVS1 assessment. NM_007294.4:c.2342A>C is a missense variant producing p.Glu781Ala, not a PTC variant, so neither classic missense PM5 nor PM5_PTC applies.

Rule
Classic missense PM5 is not used by ENIGMA; PM5_VariableWeight is restricted to genomic PTC variants annotated with PVS1 and weighted by exon.
Evidence considered
  • ENIGMA states that classic missense PM5 is not used and is considered within BP1, BP4, and PP3.
  • ENIGMA repurposes PM5 as PM5_VariableWeight (PTC), applicable only to genomic protein-termination-codon variants annotated with PVS1.
  • The case variant is a missense substitution, NM_007294.4:c.2342A>C (p.Glu781Ala), not a PTC variant.
Still missing
  • No exact variant entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt; this table governs PM5_PTC and PVS1 exon weights.
  • No exact variant entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18vcep_specifications_table4_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18
PM6 VCEPNot applicable: ENIGMA explicitly prohibits PM6 because de novo occurrences lack calibration in BRCA1/2-related cancers. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 VCEP specification explicitly states that PM6 is not to be used for BRCA1/2-related cancers because these cancers occur relatively commonly and there is no information to calibrate the predictive capacity of de novo occurrences without confirmed paternity and maternity. No PM6 evidence can therefore be assigned under this governing framework.

VCEP rule
Do not use PM6 for BRCA1/2-related cancers; no calibration exists for de novo occurrences without confirmed paternity and maternity.
Evidence considered
  • ENIGMA BRCA1/2 VCEP Specification v1.2 Table 1 assigns PM6 as do not use and gives the reason that BRCA1/2-related cancers occur relatively commonly without calibrated de novo predictive capacity.
Sources
cspec ↗
PP2 VCEPNot applicable: ENIGMA explicitly excludes PP2 because missense variants are not a common BRCA1 pathogenic mechanism. Details ▾Hide ▴
Reasoning

The governing ENIGMA BRCA1 specification explicitly marks PP2 as not applicable because missense variants are not a common mechanism of pathogenicity for BRCA1 and BRCA2, despite the generic PP2 formulation concerning low benign missense variation.

VCEP rule
ENIGMA PP2 is not applicable to BRCA1/2.
Evidence considered
  • ENIGMA Table 1 marks PP2 as Do not use and states that BRCA1/2 missense variants are not a common mechanism of pathogenicity.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
PP5 VCEPNot applicable: ClinVar has no exact-variant Expert Panel Pathogenic or Likely pathogenic classification eligible for PP5. Details ▾Hide ▴
Reasoning

The ENIGMA specification marks PP5 as do not use. Under the requested override, PP5 may be applied only for an exact-variant ClinVar Expert Panel classification of Pathogenic or Likely pathogenic. ClinVar variation 156186 has no Expert Panel submissions; the recorded submissions are ordinary laboratory or other non-expert assertions and are predominantly Uncertain significance, with one non-expert Likely benign submission. Therefore no PP5 evidence is eligible.

VCEP rule
PP5 is eligible only for an exact-variant ClinVar Expert Panel Pathogenic or Likely pathogenic classification; ENIGMA otherwise says do not use PP5.
Evidence considered
  • The ENIGMA specification states PP5 is not used.
  • ClinVar variation 156186 has expert_panels={} and expert_panel_submissions=0.
  • The available exact-match ClinVar submissions are non-expert assertions; aggregate or ordinary laboratory labels cannot trigger PP5.
Sources
cspec ↗clinvar ↗
BP2 VCEPNot applicable: the BRCA1 VCEP explicitly says not to use BP2 and limits it to BS2, with no BP2 strength assigned. Details ▾Hide ▴
Reasoning

The ENIGMA BRCA1/2 VCEP specification explicitly says not to use BP2 and states that it is applied only in the context of BS2. The specification describes the generic observation as the assessed variant being in trans with a pathogenic variant in a fully penetrant dominant disorder or in cis with a pathogenic variant in any inheritance pattern, but provides no applicable BP2 strength for BRCA1. Accordingly, BP2 is not applicable under the governing VCEP framework regardless of the absence of variant-specific phase evidence.

VCEP rule
Do not use BP2 for BRCA1; it is applied only in the context of BS2.
Evidence considered
  • ENIGMA BRCA1/2 VCEP Specifications V1.2 Table 1 states for BP2: 'Do not use' and 'Applied only in the context of BS2.'
  • The consolidated case-evidence bundle reproduces the governing BP2 rule as not applicable and provides no BRCA1 BP2 strength rule.
Still missing
  • No entry for c.2342A>C, p.Glu781Ala, or p.E781A was found in Specifications_V1.2_2024-11-18.docx.txt; the governing document supplies a blanket BP2 exclusion rather than a variant-specific assignment.
Sources
cspec ↗
BP3 VCEPNot applicable: p.Glu781Ala is a missense change, not an in-frame insertion or deletion in a repetitive region without known function. Details ▾Hide ▴
Reasoning

NM_007294.4:c.2342A>C is a missense substitution, p.Glu781Ala, rather than an in-frame deletion or insertion. It therefore does not meet the generic BP3 event definition of an in-frame deletion/insertion in a repetitive region without known function. The ENIGMA BRCA1 VCEP specification explicitly states that BP3 is not used and that the relevant benign computational/domain assessment is captured elsewhere. No repeat-region length change or variant-specific BP3 assignment is present, and the governing ENIGMA files contain no entry for c.2342A>C, p.Glu781Ala, or p.E781A.

VCEP rule
ENIGMA BRCA1 VCEP v1.2: BP3 do not use; the variant is not an in-frame insertion/deletion.
Evidence considered
  • The case annotation identifies p.Glu781Ala as a missense substitution, with no in-frame insertion/deletion or repeat-region length change.
  • The ENIGMA BRCA1 specification states that BP3 is not used and defines the underlying criterion as an in-frame deletion or insertion in a repetitive region without known function.
  • The searched ENIGMA Table 4, full specification, appendices, and Houdayer paper contained no variant-specific entry for c.2342A>C, p.Glu781Ala, or p.E781A.
Still missing
  • No c.2342A>C, p.Glu781Ala, or p.E781A entry was found in Specifications_Table4_V1.2_2024-11-18.xlsx.txt.
  • No c.2342A>C, p.Glu781Ala, or p.E781A entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No c.2342A>C, p.Glu781Ala, or p.E781A entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No c.2342A>C, p.Glu781Ala, or p.E781A entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗vcep_specifications_v1_2_2024_11_18
BP6 VCEPNot applicable: ClinVar has no exact-variant Expert Panel Benign or Likely benign classification eligible for BP6. Details ▾Hide ▴
Reasoning

The ENIGMA specification marks BP6 as do not use. Under the requested override, BP6 may be applied only for an exact-variant ClinVar Expert Panel classification of Benign or Likely benign. ClinVar variation 156186 has no Expert Panel submissions; its one Likely benign assertion is a non-expert single-submitter record and cannot trigger BP6.

VCEP rule
BP6 is eligible only for an exact-variant ClinVar Expert Panel Benign or Likely benign classification; ENIGMA otherwise says do not use BP6.
Evidence considered
  • The ENIGMA specification states BP6 is not used.
  • ClinVar variation 156186 has expert_panels={} and expert_panel_submissions=0.
  • The single exact-match Likely benign submission is a non-expert single-submitter assertion and cannot trigger BP6.
Sources
cspec ↗clinvar ↗
BP7 N/ANot applicable: c.2342A>C is missense, whereas BP7 is restricted to synonymous variants. Details ▾Hide ▴
Reasoning

BP7 applies only to synonymous variants. NM_007294.4:c.2342A>C is a missense variant encoding p.(Glu781Ala), so BP7 is not applicable and no splice or conservation prediction is evaluated for this criterion.

Rule
BP7 is applicable only to synonymous variants or qualifying intronic variants under the ENIGMA specification; a missense variant is not applicable.
Evidence considered
  • The case normalization identifies NM_007294.4:c.2342A>C as missense p.(Glu781Ala).
  • The ENIGMA BRCA1/2 VCEP v1.2 specification restricts BP7 to silent or qualifying intronic variants; this missense variant is outside BP7 scope.
Sources
cspec ↗

Identifiers

Gene
BRCA1
Transcript
NM_007294.4
Coding (HGVS c.)
NM_007294.4:c.2342A>C
Protein (HGVS p.)
NP_009225.1:p.(Glu781Ala)
GRCh38
chr17:43093189 T>G
GRCh37
chr17:41245206 T>G
Location and type
Exon 10 · missense
ClinVar
491052, 156186

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 13 / 1,613,960 alleles AF 8.05e-06 · 0 homozygotes · FAF 5.42e-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 8.1e-06 · 13 / 1,613,960 alleles · 0 hom · FAF 5.4e-06
Remaining individuals1 / 62,506 1.6e-05
European (non-Finnish)12 / 1,179,968 1e-05
0 alternate alleles recorded in 8 other groups: 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= 8.05472e-06; MAF= 0.00081%, 13/1613960 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.59985e-05; MAF= 0.00160%, 1/62506 alleles, homozygotes = 0); grpmax FAF= 5.42e-06.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -120 bp
0.000
SpliceAI acceptor gainat +167 bp
0.001
SpliceAI donor lossat -61 bp
0.001
SpliceAI donor gainat +2 bp
0.018
Pangolin splice lossmagnitude shown
-0.004
Pangolin splice gain
0.055

Other predictors

REVEL
0.423
BayesDel
-0.117

How the predictions were used

PP3 Not met: missense REVEL score 0.423 is below the >=0.644 supporting PP3 threshold. Details ▾Hide ▴
Reasoning

NM_007294.4:c.2342A>C is a missense variant encoding p.(Glu781Ala), so this group's applicable computational path is REVEL only; SpliceAI is not used for missense PP3/BP4 assessment. The REVEL score is 0.423, below the generic ClinGen SVI supporting PP3 threshold of >=0.644 from Pejaver et al. 2022 (PMID:36413997), and therefore PP3 is not met. No exact entry for c.2342A>C, p.Glu781Ala, or p.E781A was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.

Rule
For a missense variant, evaluate PP3 using REVEL only; supporting PP3 requires REVEL >=0.644 under the supplied ClinGen SVI calibration.
Evidence considered
  • The case normalization identifies NM_007294.4:c.2342A>C as the missense substitution NP_009225.1:p.(Glu781Ala), so REVEL is the applicable computational path and SpliceAI is not used for PP3.
  • The local REVEL result is 0.423; the supplied ClinGen SVI calibration assigns supporting PP3 at REVEL >=0.644 (Pejaver et al. 2022, PMID:36413997), so the score does not meet PP3.
  • The ENIGMA BRCA1/2 VCEP v1.2 specification governs PP3/BP4/BP7; the requested variant notations were searched in all four declared full-text VCEP files and no exact entry was found.
Still missing
  • No exact c.2342A>C, p.Glu781Ala, or p.E781A entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No exact c.2342A>C, p.Glu781Ala, or p.E781A entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.2342A>C, p.Glu781Ala, or p.E781A entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.2342A>C, p.Glu781Ala, or p.E781A entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗revelvcep_supplementarytables_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18
BP4 Not met: missense REVEL score 0.423 exceeds the <=0.29 supporting BP4 threshold and is therefore gray-zone. Details ▾Hide ▴
Reasoning

NM_007294.4:c.2342A>C is a missense variant encoding p.(Glu781Ala), so this group's applicable computational path is REVEL only; SpliceAI is not used for missense PP3/BP4 assessment. The REVEL score is 0.423, above the generic ClinGen SVI supporting BP4 threshold of <=0.29 from Pejaver et al. 2022 (PMID:36413997), placing it in the gray zone; BP4 is not met and the available SpliceAI score cannot substitute. No exact entry for c.2342A>C, p.Glu781Ala, or p.E781A was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt, Specifications_V1.2_2024-11-18.docx.txt, Appendices_V1.2_2024-11-18.docx.txt, or PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.

Rule
For a missense variant, evaluate BP4 using REVEL only; supporting BP4 requires REVEL <=0.29 under the supplied ClinGen SVI calibration, and a gray-zone result does not permit substitution of SpliceAI.
Evidence considered
  • The case normalization identifies NM_007294.4:c.2342A>C as the missense substitution NP_009225.1:p.(Glu781Ala), so REVEL is the applicable computational path and SpliceAI is not used for BP4.
  • The local REVEL result is 0.423; the supplied ClinGen SVI calibration assigns supporting BP4 at REVEL <=0.29 (Pejaver et al. 2022, PMID:36413997), so the score is gray-zone and does not meet BP4.
  • The ENIGMA BRCA1/2 VCEP v1.2 specification governs PP3/BP4/BP7; the requested variant notations were searched in all four declared full-text VCEP files and no exact entry was found.
Still missing
  • No exact c.2342A>C, p.Glu781Ala, or p.E781A entry was found in SupplementaryTables_V1.2_2024-11-18.xlsx.txt.
  • No exact c.2342A>C, p.Glu781Ala, or p.E781A entry was found in Specifications_V1.2_2024-11-18.docx.txt.
  • No exact c.2342A>C, p.Glu781Ala, or p.E781A entry was found in Appendices_V1.2_2024-11-18.docx.txt.
  • No exact c.2342A>C, p.Glu781Ala, or p.E781A entry was found in PMID_22505045_Houdayer_2012_HumMutat.pdf.txt.
Sources
cspec ↗revelvcep_supplementarytables_v1_2_2024_11_18vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18
BP7 N/ANot applicable: c.2342A>C is missense, whereas BP7 is restricted to synonymous variants. Details ▾Hide ▴
Reasoning

BP7 applies only to synonymous variants. NM_007294.4:c.2342A>C is a missense variant encoding p.(Glu781Ala), so BP7 is not applicable and no splice or conservation prediction is evaluated for this criterion.

Rule
BP7 is applicable only to synonymous variants or qualifying intronic variants under the ENIGMA specification; a missense variant is not applicable.
Evidence considered
  • The case normalization identifies NM_007294.4:c.2342A>C as missense p.(Glu781Ala).
  • The ENIGMA BRCA1/2 VCEP v1.2 specification restricts BP7 to silent or qualifying intronic variants; this missense variant is outside BP7 scope.
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.423. BayesDel score = -0.116509.

7 paper records listed. 2 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.

Cited in the classification

  • Easton et al. 2007 BRCA1/2 multifactorial likelihood assessment
    Easton et al. established the multifactorial BRCA1/2 likelihood framework in which co-occurrence, personal/family history, and cosegregation likelihood ratios can be combined; it is methodological context for the ENIGMA PP4/BP5 framework and does not provide an exact-variant result for c.2342A>C.
    → PP4 · supporting Does not name this variant
    PMID 17924331 ↗
    Source detail
    For each of these factors, a likelihood ratio was computed under the hypothesis that the VUSs were equivalent to an ‘average’ deleterious mutation, compared with neutral, with respect to risk. The likelihood ratios derived from each component were combined to provide an overall assessment for each VUS.

    Location Abstract, page 1

    Context Systematic assessment of 1,433 BRCA1/2 sequence variants of unknown significance using co-occurrence, personal/family-history logistic regression, and cosegregation data from large clinical-testing datasets.

  • Li et al. 2020 BRCA1/2 clinical-history likelihood-ratio model
    Li et al. developed a BRCA1/2 personal- and family-history logistic-regression model from multigene-panel testing and calculated a per-variant clinical-history likelihood ratio by multiplying the individual likelihood ratios for probands carrying that variant; the exact gene-specific table row for BRCA1 c.2342A>C reports LR=3.158578379510139 from one proband.
    → PP4 · supporting Names this variant
    PMID 31853058 ↗
    Source detail
    For each variant, LRs were multiplied for each individual carrying that variant (potentially in different race/ethnicity groups) to arrive at a per-variant LR.

    Location Methods, BRCA prediction models, page 2

    Context Retrospective logistic-regression analysis of 138,342 eligible multigene-panel-tested individuals, stratified by gene and four racial/ethnic groups; the exact variant-level LR was taken from the gene-specific supplementary clinical-history table.

Other recorded publications

  • Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.
    No paper-specific finding is recorded.
    PMID 23918944 ↗
  • 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 ↗
  • Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots".
    Dines JN et al. · 2020
    Dines et al. analyzed ClinVar BRCA1 missense variants and identified exon 11, which contains residue 781, as a coldspot with no confirmed pathogenic or likely pathogenic missense variants; the estimated pathogenicity odds ratio for missense variants in exon 11 was below 0.01.
    Does not name this variant
    PMID 31911673 ↗
    Quoted passage
    By contrast, exon 11 accounts for ~60% of the coding sequence but has no confirmed P + LP missense variants, and 58.0% (69/119) of B + LB variants. The estimated odds ratio for pathogenicity of missense variants in exon 11 is <0.01 (95% confidence interval [CI] 0.0–0.01, which satisfies the criteria for “strong benign” evidence, Table 2).18 Therefore, we classify this region as a coldspot.

    Results, BRCA1 section, paragraph discussing exon 11

  • Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021.
    No paper-specific finding is recorded.
    PMID 34242744 ↗
  • Fanconi Anemia.
    No paper-specific finding is recorded.
    PMID 20301575 ↗
  • ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.
    No paper-specific finding is recorded.
    PMID 25356965 ↗
  • ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG).
    No paper-specific finding is recorded.
    PMID 34012068 ↗

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

gnomAD v4.1 13 / 1,613,960 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.018 Open source ↗
ClinVar 7 Uncertain significance · 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= 8.05472e-06; MAF= 0.00081%, 13/1613960 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.59985e-05; MAF= 0.00160%, 1/62506 alleles, homozygotes = 0); grpmax FAF= 5.42e-06.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (7 clinical laboratories) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 156186)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.423. BayesDel score = -0.116509.

Functional

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

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.