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
Final classification
Likely Pathogenic
PVS1PP4PP5
BRCA1
c.5194-12G>A
p.?
This variant
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 ↗
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 · 3 applied · 12 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 · 3
Strength
Supporting
Moderate
Strong
Very strong
PVS1
strong
review
Pathogenic
This intronic variant is outside the canonical +/-1,2 splice site, so default generic PVS1 does not apply. However, BRCA1 loss of function is an established disease mechanism, and RNA studies showed retention of 10 nucleotides of intron 19 (r.5193_5194ins5194-10_5194-1), consistent with a loss-of-function transcript. Under the ENIGMA BRCA1/2 RNA-splicing framework, this supports PVS1 at Strong strength.
BRCA1 loss of function is an established disease mechanism in the ENIGMA framework.Splicing studies reported retention of 10 nt of intron 19.The variant is outside the canonical +/-1
PP4
moderate
Pathogenic
Clinical-history likelihood-ratio analysis for BRCA1 reported an LR of 12.3447 in 1 proband for this variant. This value is above the ENIGMA PP4_Moderate threshold of 4.3 and below the PP4_Strong threshold of 18.7, supporting PP4 at Moderate strength.
Clinical-history LR 12.3447196932389N_Probands 1
Assessed · not applied
· 6 not met · 6 not assessed
Pathogenic
PS1
No evidence was identified that this variant is predicted to produce the same protein change or the same splice consequence as a different previously classified pathogenic or likely pathogenic BRCA1 variant under ENIGMA PS1 rules.
PS4
No case-control study showing a statistically increased prevalence of this variant in affected individuals versus controls was identified.
PM2
This variant is absent from gnomAD v2.1 and present at very low frequency in gnomAD v4.1 (2/1612068 alleles; AF 1.24064e-06; grpmax FAF 2.8e-07).
PM3
No evidence was identified that this variant was observed in trans with another BRCA1 pathogenic variant in an individual with BRCA1-related Fanconi anemia.
PP1
No quantitative co-segregation data were identified for this variant.
Benign
BA1
The highest observed filter allele frequency is 2.8e-07 in gnomAD v4.1, which is below the ENIGMA BA1 threshold of 0.001.
BS1
The highest observed filter allele frequency is 2.8e-07 in gnomAD v4.1, which is below the ENIGMA BS1_Supporting threshold of 0.00002 and well below the BS1 threshold of 0.0001.
BS2
No data were identified showing this variant in individuals without features of BRCA1-related Fanconi anemia at the point thresholds required for BS2.
BS4
No quantitative evidence for lack of segregation in affected family members was identified for this variant.
BP4
For intronic variants outside the native splice sites, ENIGMA BP4 requires no predicted splice impact with SpliceAI <=0.1.
BP5
Clinical-history likelihood-ratio analysis reported an LR of 12.3447 in 1 proband for this variant.
BP7
ENIGMA BP7 is used for variants with no predicted splice impact or for mRNA studies showing no damaging splice effect.
N/A · 13
PS2 · PS3 · PM1 · PM4 · PM5 · PM6 · PP2 · PP3 · BS3 · BP1 · BP2 · BP3 · BP6
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.
Splicing and multifactorial analysis of intronic BRCA1 and BRCA2 sequence varian
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1
strong
Contribution of bioinformatics predictions and functional splicing assays to the
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1
strong
Li et al. 2020 BRCA1/2 clinical-history likelihood-ratio model
Found
Structured finding pending for this record — see source link.
Applied to
→PP4
moderate
Sources & reference links