PM2 (supporting): The NM_032043.3:c.476A>C (p.Lys159Thr) missense variant in BRIP1 is absent from all large population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting level in the generic ACMG/AMP 2015 framework.1 BP1 (supporting benign): BRIP1 is a gene for which loss of function is the established disease mechanism. Truncating variants represent the primary pathogenic spectrum. This missense variant is not a predicted null variant, applying BP1 at supporting benign level.2 BP4 (supporting benign): Multiple computational predictors (REVEL 0.311, BayesDel 0.027, SpliceAI max delta 0.05) converge on a benign prediction with no evidence of splicing disruption, meeting BP4 at supporting benign level.3 The variant has one supporting pathogenic criterion (PM2) and two supporting benign criteria (BP1, BP4). Per ACMG/AMP 2015 combination rules, criteria at the supporting level in opposing directions do not sum to a definitive classification, and the variant is classified as a variant of uncertain significance (VUS).4
BRIP1
Final classification
Likely Benign
PM2BP1BP4
BRIP1
c.476A>C
p.Lys159Thr
This variant
PM2 (supporting): The NM_032043.3:c.476A>C (p.Lys159Thr) missense variant in BRIP1 is absent from all large population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting level in the generic ACMG/AMP 2015 framework.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP1 supporting benign, BP4 supporting benign; combination = 1 supporting + 2 supporting benign, which maps to Likely Benign.
Classification rationale
PM2
BP1BP4
Likely Benign
BRIP1 c.476A>C
PM2 + BP1 + BP4
→
Likely Benign
2
pvs1_gene_contextpvs1_generic_framework ↗
3
revelbayesdelspliceai ↗
4
generic_acmg_combination_rules
Gene diagram
· NM_032043.3 · variants mapped to exon structure
BRIP1
NM_032043.3
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 20 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
✓
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0 (HostSeq genomes). In a non-VCEP/generic ACMG framework, complete absence from large population databases at a position with adequate coverage supports PM2 at supporting level (allele frequency <0.1%).
Absent from gnomAD v2.1 (exomes).Absent from gnomAD v4.1 (exomes/genomes).Absent from gnomAD-Canada v1.0 (HostSeq genomes).
✓
BP1
supporting
Benign
BRIP1 is a gene for which loss of function is the established disease mechanism, with truncating variants (nonsense, frameshift, canonical splice) representing the primary pathogenic variant spectrum. This is a missense variant (p.Lys159Thr) in a gene where primarily truncating variants cause disease, supporting a benign interpretation per BP1.
BRIP1 loss of function is the established germline disease mechanism (Fanconi anemiahereditary breast/ovarian cancer).Supporting literature (PMID:41070818) confirms BRIP1 as a moderate-penetrance cancer predisposition gene where pathogenic variants are predominantly truncating.
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.311 (below the 0.5 pathogenic threshold), BayesDel score is 0.027 (strongly benign-leaning), and SpliceAI predicts no splicing alteration (max delta 0.05). The convergent in silico evidence supports BP4 at supporting benign level.
REVEL: 0.311 (below pathogenic threshold).BayesDel: 0.027 (benign-leaning prediction).SpliceAI: max delta 0.05 (no predicted splice impact).
Assessed · not applied
· 19 not met · 1 not assessed
Pathogenic
PS1
No known pathogenic variant with the identical amino acid change (p.Lys159Thr) has been identified in ClinVar or the literature.
PS2
No de novo observation with confirmed paternity and maternity was identified for this variant.
PS3
No well-established in vitro or in vivo functional studies supportive of a damaging effect were identified for this variant.
PS4
No case-control or cohort data demonstrating statistically significant enrichment of this variant in affected individuals versus controls were identified.
PM1
The variant does not lie within a statistically significant mutational hotspot (CancerHotspots negative) and is not located in a well-characterized functional domain without benign variation.
PM5
No missense variant at the same amino acid residue (p.Lys159) with an established pathogenic classification was identified.
PM6
No de novo observation was identified for this variant.
PP1
No co-segregation data in affected family members was identified.
PP2
PP2 requires demonstration that the gene has a low rate of benign missense variation (e.g., high missense constraint Z-score) and that missense variants are a common disease mechanism.
PP3
Multiple lines of computational evidence do not support a deleterious effect.
PP4
No patient phenotype or family history data were available.
PP5
No reputable source has recently reported this variant as pathogenic.
Benign
BA1
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1
The variant is absent from all population databases (gnomAD v2.1, v4.1, Canada).
BS2
No observation of this variant in a homozygous state in healthy adults was identified.
BS3
No well-established in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing were identified.
BS4
No lack of segregation in affected family members was identified.
BP2
No phase data were available.
BP5
No data were available indicating an alternate molecular basis for disease in a patient carrying this variant.
BP6
No reputable source has reported this variant as benign or likely benign.
N/A · 3
PVS1 · BP3 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.311. BayesDel score = 0.0269509.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRIP1, a DEAH helicase, is altered by mutation and amplification in various cancers, including breast cancer and melanoma.
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