The BRCA1 c.5200T>A (p.Phe1734Ile; p.F1734I) variant has not been observed in COSMIC and has been reported in ClinVar, where the ClinGen ENIGMA BRCA1/2 expert panel classifies it as likely pathogenic.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity, although the ENIGMA PM2_Supporting rule was not formally established from the available depth-specific evidence.2 In a calibrated BRCA1 functional study, saturation genome editing showed loss of function similar to pathogenic control variants, and the ENIGMA BRCA1/2 specification assigns PS3 at Strong strength.3 This missense change is located in the BRCA1 BRCT repeats; REVEL is 0.871, but under the ENIGMA computational rule the observed BayesDel score of 0.242362 and SpliceAI max delta score of 0.00 do not meet PP3 or BP4 thresholds.4
Final classification
VUS
PS3PP5
BRCA1
c.5200T>A
p.Phe1734Ile
This variant
The BRCA1 c.5200T>A (p.Phe1734Ile; p.F1734I) variant has not been observed in COSMIC and has been reported in ClinVar, where the ClinGen ENIGMA BRCA1/2 expert panel classifies it as likely pathogenic.
ENIGMA BRCA1 and BRCA2 Specification v1.2.0 final-classification framework (Table 3 criteria-combination rules).
Classification rationale
PS3PP5
VUS
BRCA1 c.5200T>A
PS3 + PP5
→
VUS
3
vcep_specifications_table9_v1_2_2024_11_18PMID:30209399 ↗
4
revelbayesdelspliceai ↗cspec ↗vcep_appendices_v1_2_2024_11_18
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_007294.3 · variants mapped to exon structure
BRCA1
NM_007294.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 15 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
PS3
strong
Pathogenic
In a calibrated BRCA1 functional study, this variant showed loss of function similar to pathogenic control variants. The ENIGMA BRCA1/2 specification assigns PS3 at Strong strength for BRCA1 c.5200T>A (p.Phe1734Ile).
Specifications Table 9 row for BRCA1 c.5200T>A assigns PS3 Strong.Supplementary functional dataset records c.5200T>A as Functional impact - complete / LOF.
Assessed · not applied
· 8 not met · 7 not assessed
Pathogenic
PS1
No validated evidence was identified showing that this variant has the same amino acid change as a previously classified pathogenic or likely pathogenic variant, or the same predicted splice effect as a known pathogenic variant.
PS4
No case-control study or other quantitative enrichment analysis was identified showing that this variant is significantly more common in affected individuals than controls at the ENIGMA PS4 threshold.
PM2
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports rarity.
PM3
No evidence was identified for biallelic BRCA1 disease or a Fanconi anemia context with this variant.
PP1
No segregation data were identified for this variant, so PP1 was not assessed.
PP3
This missense variant lies in the BRCA1 BRCT repeats, but the ENIGMA computational threshold for PP3 is not met.
PP4
A BRCA1 clinical-history likelihood ratio was identified for this variant, but it does not reach the ENIGMA PP4 threshold.
Benign
BA1
This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the ENIGMA BA1 frequency threshold of filter allele frequency greater than 0.1%.
BS1
This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the ENIGMA BS1 frequency thresholds of filter allele frequency greater than 0.002% or greater than 0.01%, depending on strength.
BS2
No proband-level data were identified showing this variant in individuals without features of BRCA1-related Fanconi anemia under the ENIGMA point-based framework.
BS3
Available functional evidence does not support normal BRCA1 function for this variant.
BS4
No lack-of-segregation data were identified for this variant, so BS4 was not assessed.
BP1
This missense variant is within the BRCA1 BRCT repeats, a clinically important functional domain, so it does not meet the ENIGMA BP1 requirement for a variant outside a clinically important domain.
BP4
This missense variant is within the BRCA1 BRCT repeats, but benign computational evidence is insufficient for BP4.
BP5
A BRCA1 clinical-history likelihood ratio was identified for this variant, but it does not meet the ENIGMA BP5 threshold.
N/A · 11
PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · BP2 · BP3 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (3 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as Pathogenic (1 clinical laboratory) and as Likely Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 232047)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.871. BayesDel score = 0.242362.
Functional
Likely Oncogenic
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
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.
Accurate classification of BRCA1 variants with saturation genome editing.
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
strong
Sources & reference links
Triaged references · 8 PMIDs not cited in assessment
23918944 ↗
Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.
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
26467025 ↗
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
CLINVAR
31853058 ↗
Classification of variants of uncertain significance in BRCA1 and BRCA2 using personal and family history of cancer from individuals in a large hereditary cancer multigene panel testing cohort.
CLINVAR
35196514 ↗
The functional impact of BRCA1 BRCT domain variants using multiplexed DNA double-strand break repair assays.
CLINVAR
15604628 ↗
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
CLINVAR
17392385 ↗
American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR