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
BRCA1
Final classification
VUS
BRCA1 c.5200T>A · p.Phe1734Ile
BRCA1
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
Gene diagram
· NM_007294.3 · variants mapped to exon structure
BRCA1
NM_007294.3
Fetching transcript structure from UCSC…
Applied criteria · 2 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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. 9 further PMIDs triaged but not cited — see Sources & References.
PMID PMID:30209399
Found
Structured finding pending for this record — see source link.
Applied to
→PS3 supports · met
Sources & reference links
Triaged references · 9 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