The BRCA1 c.5522G>A (p.Ser1841Asn; p.S1841N) variant has been reported in ClinVar with conflicting interpretations, including an expert-panel classification of uncertain significance.1 This variant is absent from gnomAD v2.1 and present once in gnomAD v4.1 (1/1,614,094 alleles; AF 6.20e-07; highest South Asian AF 1.10e-05), so it is very rare but not absent from population databases.2 In ENIGMA-calibrated functional studies, results were discordant, ranging from loss-of-function to intermediate effects, and ENIGMA Table 9 does not assign PS3 or BS3 for this variant.3 This missense change lies in the BRCA1 BRCT repeats, and the BRCA1 ENIGMA computational rule supports BP4 because BayesDel no-AF is 0.144191 (threshold <=0.15) and SpliceAI maximum delta is 0.00 (threshold <=0.1); REVEL is 0.626 but is not the deciding rule in this VCEP framework.4
Final classification
Uncertain Significance
BP4
BRCA1
c.5522G>A
p.Ser1841Asn
This variant
The BRCA1 c.5522G>A (p.Ser1841Asn; p.S1841N) variant has been reported in ClinVar with conflicting interpretations, including an expert-panel classification of uncertain significance.
Official ENIGMA BRCA1 and BRCA2 Specification v1.2 Table 3 final-classification combination rules (CSPEC/VCEP framework).
Classification rationale
BP4
Uncertain Significance
BRCA1 c.5522G>A
BP4
→
Uncertain Significance
3
vcep_specifications_table9_v1_2_2024_11_18vcep_supplementarytables_v1_2_2024_11_18
4
vcep_specifications_v1_2_2024_11_18vcep_appendices_v1_2_2024_11_18bayesdelspliceai ↗revel
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 · 1 applied · 16 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 · 1
Strength
Supporting
Moderate
Strong
Very strong
BP4
supporting
review
Benign
This missense variant is located in the BRCA1 BRCT repeats, and the BRCA1 ENIGMA BP4 rule is met because BayesDel no-AF is 0.144191, which is at or below the benign threshold of 0.15, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.00, which is at or below the threshold of 0.1. REVEL is 0.626, but the gene-specific BRCA1 VCEP computational rule is based on BayesDel and SpliceAI rather than REVEL.
Protein location within BRCT repeatsBayesDel no-AF 0.144191 <= 0.15SpliceAI max delta 0.00 <= 0.1
Assessed · not applied
· 8 not met · 8 not assessed
Pathogenic
PVS1
This variant is a missense substitution, p.(Ser1841Asn) / p.(S1841N), and does not fall into the BRCA1 loss-of-function variant categories used for PVS1.
PS1
No evidence was identified showing that this variant produces the same established pathogenic protein or splicing consequence as another previously classified BRCA1 variant, so PS1 was not assessed.
PS3
ENIGMA-calibrated functional evidence for this variant is discordant across multiple studies, with reported results ranging from loss-of-function to intermediate effects.
PS4
No case-control analysis or formal evidence showing that this variant is significantly enriched in affected individuals compared with controls was identified, so PS4 was not assessed.
PM2
This variant is absent from gnomAD v2.1 but is present in gnomAD v4.1 at 1/1,614,094 alleles (AF 6.20e-07; highest population AF 1.10e-05 in South Asian individuals).
PM3
No evidence was identified that this variant was observed with an appropriate BRCA1-related Fanconi anemia phenotype and a qualifying second BRCA1 variant in trans, so PM3 was not assessed.
PP1
No quantitative co-segregation data were identified for this variant, so PP1 was not assessed.
PP3
This missense variant is located in the BRCA1 BRCT repeats, but the BRCA1 ENIGMA PP3 rule is not met because BayesDel no-AF is 0.144191, which is below the pathogenic threshold of 0.28, and SpliceAI predicts no splice effect with a maximum delta score of 0.00, below the splicing threshold of 0.2.
PP4
No variant-specific multifactorial clinical-history likelihood ratio meeting the BRCA1 ENIGMA PP4 thresholds was identified for this variant, so PP4 was not assessed.
Benign
BA1
This variant does not meet the BRCA1 ENIGMA BA1 threshold.
BS1
This variant does not meet the BRCA1 ENIGMA BS1 threshold.
BS2
No qualifying data were identified showing this variant in individuals without features of BRCA1-related Fanconi anemia under the BRCA1 ENIGMA point-based BS2 framework, so BS2 was not assessed.
BS3
ENIGMA-calibrated functional studies for this variant are discordant and do not consistently show a normal or non-damaging effect.
BS4
No quantitative non-segregation data were identified for this variant, so BS4 was not assessed.
BP1
This missense variant is located in the BRCA1 BRCT repeats, a clinically important functional domain spanning amino acids 1650-1857, so it does not meet the BRCA1 ENIGMA BP1 rule for missense variants outside important domains.
BP5
No variant-specific multifactorial clinical-history likelihood ratio meeting the BRCA1 ENIGMA BP5 thresholds was identified for this variant, so BP5 was not assessed.
N/A · 11
PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.19543e-07; MAF= 0.00006%, 1/1614094 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09798e-05; MAF= 0.00110%, 1/91076 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.2e-05%
· 1 / 1,614,094
0 hom
0 hom
South Asian 1 / 91,076 |
0.0011% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish))
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 (4 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Pathogenic (1 clinical laboratory) and as likely pathogenic (1 clinical laboratory) and as Uncertain Significance by ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.626. BayesDel score = 0.144191.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
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.
Sources & reference links