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LYFE SCIENCES
Project: HERA
NM_007294.3:c.5522G>A
p.Ser1841Asn  ·  BRCA1
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Classification rationale
1

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.

clinvar ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗
3

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.

4

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.

spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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—
Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
—
Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1Absent from gnomAD v2.1.
gnomAD v4.1This 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).
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
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).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.626. BayesDel score = 0.144191.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueS1841
Hotspots ↗