The BRCA1 c.5194-12G>A (p.?) variant has been reported in ClinVar, where the ClinGen ENIGMA expert panel classified it as pathogenic.1 This variant is absent from gnomAD v2.1 and is present at very low frequency in gnomAD v4.1 (2/1612068 alleles; AF 1.24064e-06; grpmax FAF 2.8e-07).2 RNA studies showed retention of 10 nucleotides of intron 19 (r.5193_5194ins5194-10_5194-1), which is consistent with a loss-of-function splice effect and supports PVS1 at Strong strength under the ENIGMA BRCA1/2 RNA framework.3 SpliceAI predicts a strong splice impact for this variant with a maximum delta score of 0.96.4 In the ENIGMA BRCA1 clinical-history model, this variant had a likelihood ratio of 12.3447 in 1 proband, which meets PP4 at Moderate strength.5
BRCA1
Final classification
Likely Pathogenic
BRCA1 c.5194-12G>A · p.?
BRCA1
The BRCA1 c.5194-12G>A (p.?) variant has been reported in ClinVar, where the ClinGen ENIGMA expert panel classified it as pathogenic.
ClinGen ENIGMA BRCA1 and BRCA2 Specification v1.2.0 final-classification framework using Table 3 adapted ACMG/AMP criteria-combination rules
Classification rationale
PVS1PP4PP5
Likely Pathogenic
BRCA1 c.5194-12G>A
PVS1 + PP4 + PP5
→
Likely Pathogenic
3
cspec ↗vcep_appendices_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18PMID:21394826 ↗PMID:21673748 ↗
5
PMID:31853058 ↗vcep_pmid_31853058_brca1_clinical_history_lrcspec ↗
Gene diagram
· NM_007294.4 · variants mapped to exon structure
BRCA1
NM_007294.4
Fetching transcript structure from UCSC…
Applied criteria · 3 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 · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.24064e-06; MAF= 0.00012%, 2/1612068 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69739e-06; MAF= 0.00017%, 2/1178278 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00012%
· 2 / 1,612,068
0 hom · FAF 2.8e-05%
0 hom · FAF 2.8e-05%
European (non-Finnish) 2 / 1,178,278 |
0.00017% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Pathogenic (6 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Pathogenic by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.96).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Literature · how each cited paper was used
3papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
PMID PMID:21394826
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1 supports · met
PMID PMID:21673748
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1 supports · met
PMID PMID:31853058
Found
Structured finding pending for this record — see source link.
Applied to
→PP4 supports · met
Sources & reference links