Classification rationale

BS3BP1 Benign

BRCA1 c.1222A>G missense · exon 10

Benign evidence: BS3 Strong is supported by a calibrated neutral protein-function result of 0.04 for this exact variant. Benign evidence: BP1 Strong is supported because residue 408 is outside critical BRCA1 domains and SpliceAI is 0.035. The two Strong benign criteria total -8 ENIGMA points, meeting the Benign threshold of <= -7.

BS3 + BP1 → Benign

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.

Gene diagram · NM_007294.4 · variants mapped to exon structure

BRCA1 NM_007294.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 14 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

BS3 strong Benign

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

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.

cspec ↗

BP1 strong Benign

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

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.

cspec ↗PMID:31911673 ↗

Assessed · not applied · 9 not met · 5 not assessed

Pathogenic

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

PS3 Not met: ENIGMA Table 9 assigns BS3 Strong, with calibrated protein-function result 0.04 classified as likely neutral rather than damaging.

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).

PM1 Not met: Lys408 lies outside BRCA1 RING 2-101, coiled-coil 1391-1424, and BRCT 1650-1857, and VCEP PM1 is not used.

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.

PM3 Not assessed: the variant has no documented Fanconi-anemia phenotype, pathogenic partner, or qualifying trans-phase proband evidence needed for ENIGMA PM3 points.

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.

PP2 Not met: ENIGMA explicitly disallows PP2 for BRCA1 because the gene has a high frequency of benign missense variation.

PP3 Not met: missense REVEL 0.55 is below the ClinGen SVI supporting PP3 threshold of 0.644.

Benign

BA1 Not met: gnomAD v2.1 non-cancer exome AF 4.23e-06 is below the ENIGMA BA1 threshold of 0.001.

BS1 Not met: gnomAD v2.1 non-cancer exome AF 4.23e-06 is below the ENIGMA BS1-supporting lower threshold of 0.00002.

BS2 Not assessed: gnomAD shows zero homozygotes, but no qualifying phenotyped healthy-adult observations or ENIGMA BS2 point total is available.

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.

BP4 Not met: missense REVEL 0.55 exceeds the ClinGen SVI supporting BP4 threshold of <=0.29.

N/A · 12 PVS1 · PS2 · PM4 · PM5 · PM6 · PP4 · PP5 · BP2 · BP3 · BP5 · BP6 · BP7

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

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.

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).

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0025% · 41 / 1,614,214
0 hom · FAF 0.0026%

European (non-Finnish)

41 / 1,180,030

0.0035%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0004% · 1 / 250,812
0 hom

European (non-Finnish)

1 / 113,218

0.00088%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

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)

ClinVar ↗

In silico

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

SpliceAI ↗

Functional Unknown Oncogenic Effect

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.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

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

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 8 further PMIDs triaged but not cited — see Sources & references.

Rule & framework references · cited for criterion definitions, not variant evidence

31911673 ↗ Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots".

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 8 PMIDs not cited in assessment

15385441 ↗ Evolution of the tumor suppressor BRCA1 locus in primates: implications for cancer predisposition. CLINVAR

23704879 ↗ Missense variants of uncertain significance (VUS) altering the phosphorylation patterns of BRCA1 and BRCA2. CLINVAR

25741868 ↗ 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. CLINVAR

15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. CLINVAR

18163131 ↗ The emerging landscape of breast cancer susceptibility. CLINVAR

19305347 ↗ ACOG Practice Bulletin No. 103: Hereditary breast and ovarian cancer syndrome. CLINVAR

23188549 ↗ NSGC practice guideline: risk assessment and genetic counseling for hereditary breast and ovarian cancer. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

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