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
BRCA1
Final classification
Uncertain Significance
BRCA1 c.5522G>A · p.Ser1841Asn
BRCA1
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
Gene diagram
· NM_007294.3 · variants mapped to exon structure
BRCA1
NM_007294.3
Fetching transcript structure from UCSC…
Applied criteria · 1 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
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