LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-07-29
Case ID: NM_032043.3_c.736A_G_20260729_112349
Framework: ACMG/AMP 2015
Variant classification summary

NM_032043.3:c.736A>G

BRIP1  · NP_114432.2:p.(Ile246Val)  · NM_032043.3
GRCh37: chr17:59886010 T>C  ·  GRCh38: chr17:61808649 T>C
Gene: BRIP1 Transcript: NM_032043.3
Final call
VUS
PM2 supporting BP4 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
BRIP1
Transcript
NM_032043.3
Protein
NP_114432.2:p.(Ile246Val)
gnomAD AF
7.001698996340528e-05 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
NM_032043.3:c.736A>G (p.Ile246Val) in BRIP1 is a missense variant assessed under generic ACMG/AMP 2015 framework. No CSPEC/VCEP framework exists for BRIP1.
2
This variant is present at very low frequency in gnomAD (v2.1 AF=0.01553%, grpmax FAF=0.09%; v4.1 AF=0.00700%, grpmax FAF=0.087%) with no homozygotes, meeting PM2 at supporting strength.
3
Multiple in silico tools predict a benign effect: REVEL score 0.197, BayesDel score -0.206707, and SpliceAI predicts no splicing alteration (max delta 0.04), meeting BP4 at supporting strength.
4
ClinVar reports this variant as Uncertain significance by 5 clinical laboratories and Likely benign by 4 clinical laboratories (VariationID 461180). No expert panel classification is available. The ClinVar review status is 1-star and does not meet thresholds for PP5 or BP6.
5
No functional studies, segregation data, case-control data, or de novo observations were identified for this variant. Full-text review of three available publications (PMID:25741868, PMID:26467025, PMID:29641532) confirmed none mention NM_032043.3:c.736A>G.
6
The only applicable criteria are PM2 (supporting pathogenic) and BP4 (supporting benign). With one supporting pathogenic and one supporting benign criterion, the variant defaults to Uncertain Significance (VUS) under the ACMG/AMP 2015 scoring framework.
Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.
Criteria assessment
ACMG/AMP criteria review
Criteria shown when status is available
All criteria require review: For research and educational purposes only.
Criterion Status Rationale Evidence used
PVS1 N/A NM_032043.3:c.736A>G (p.Ile246Val) is a missense variant and does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798).
pvs1_generic_framework
PS1 Not met No prior pathogenic nucleotide change at the same amino acid position (p.Ile246) was identified in ClinVar or other curated sources. A different nucleotide change leading to the same missense change is required for PS1.
clinvar
PS2 Not met No de novo confirmation data are available for this variant. PS2 requires confirmed de novo occurrence with maternity and paternity confirmed.
PS3 Not met No functional studies were identified for NM_032043.3:c.736A>G (p.Ile246Val) or for a systematically characterized range that includes this residue. OncoKB reports 'Unknown Oncogenic Effect' with no curated PMIDs. One ClinVar submitter (Color Diagnostics) explicitly stated functional studies have not been reported for this variant.
oncokb clinvar
PS4 Not met No case-control prevalence data comparing affected individuals to controls are available for this variant. PS4 requires statistically significant enrichment in affected individuals over controls.
PS5 Not met No reputable source has recently reported this variant as pathogenic without access to the underlying evidence. ClinVar classification is 'Uncertain significance' or 'Likely benign' across all submissions.
clinvar
PM1 Not met Residue p.Ile246 does not lie within a statistically significant mutational hotspot (cancerhotspots.org) and no residue-specific functional domain characterization was identified in the case materials to support PM1 at domain level.
PM2 Met This variant is present at very low frequency in population databases. gnomAD v2.1 overall AF=0.01553% (39/251,202 alleles, 0 homozygotes), grpmax FAF=0.09%. gnomAD v4.1 overall AF=0.00700% (113/1,613,894 alleles, 0 homozygotes), grpmax FAF=0.087%. All frequencies are below the 0.1% PM2 threshold for non-VCEP assessment.
gnomad_v2 gnomad_v4
PM5 Not met No pathogenic missense variant at the same codon (p.Ile246) with a different amino acid change was identified in ClinVar. Automated PM5 candidate harvesting was unable to confirm classic same-residue semantics.
pm5_candidates
PM6 Not met No de novo data are available. PM6 requires a confirmed de novo observation with maternity and paternity confirmed, without confirmation of paternity and maternity.
PP1 Not met No co-segregation data in multiple affected family members are available for this variant.
PP2 Not met Insufficient constraint data are available to determine whether BRIP1 has a low rate of benign missense variation. PP2 requires a gene-specific missense Z-score or equivalent constraint metric demonstrating intolerance to missense variation.
PP3 Not met Multiple in silico tools predict no damaging effect. REVEL score is 0.197 (below the 0.5 pathogenic threshold), BayesDel score is -0.206707 (benign-leaning), and SpliceAI max delta is 0.04 (no predicted splice impact). These results do not support a deleterious prediction.
revel bayesdel spliceai
PP4 Not met No patient phenotype or family history data specific to this variant are available. PP4 requires a phenotype or family history highly specific for a disease with a single genetic etiology.
PP5 Not met ClinVar classification for this variant is 'Uncertain significance' (5 clinical laboratories) and 'Likely benign' (4 clinical laboratories) with review status 'criteria provided, single submitter' (1-star). No expert panel (3-star) classification as pathogenic exists. The ClinVar evidence does not meet PP5 threshold requiring a reputable source to classify as pathogenic.
clinvar
BA1 Not met The highest observed population frequency is 0.12% in South Asian (gnomAD v2.1 SAS), which is well below the 1% BA1 threshold. No population exceeds the BA1 cutoff.
gnomad_v2 gnomad_v4
BS1 Not met The highest observed population frequency is 0.12% in South Asian (gnomAD v2.1 SAS), which is below the 0.3% BS1 threshold for non-VCEP assessment. No population exceeds the BS1 cutoff.
gnomad_v2 gnomad_v4
BS2 Not met No homozygous observations are recorded in gnomAD (0 homozygotes in both v2.1 and v4.1). BS2 requires observation in a homozygous state or in trans with a known pathogenic variant in a gene with a recessive disorder, or observation in a healthy adult for a fully penetrant dominant disorder.
gnomad_v2 gnomad_v4
BS3 Not met No functional studies demonstrating no damaging effect on protein function or splicing were identified for this variant. OncoKB reports no curated functional evidence, and full-text review of available publications found no variant-specific functional data.
oncokb revel bayesdel
BS4 Not met No segregation data showing lack of co-segregation with disease are available for this variant.
BP1 Not met Although BRIP1 loss-of-function is a supported disease mechanism, BRIP1 is not a gene for which primarily truncating variants are known to cause disease. Pathogenic missense variants are also reported in BRIP1. BP1 requires the gene to have a disease mechanism primarily driven by truncating variants.
pvs1_gene_context
BP2 Not met No observation of this variant in trans with a known pathogenic variant in a fully penetrant dominant disorder was identified.
BP3 N/A This variant is a substitution, not an in-frame deletion or insertion in a repetitive region without a known function.
BP4 Met Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.197 (below pathogenic threshold), BayesDel score is -0.206707 (benign-leaning), and SpliceAI predicts no splicing alteration (max delta 0.04). The concordance of multiple in silico tools predicting a benign effect meets BP4 at supporting strength.
revel bayesdel spliceai
BP5 Not met No observation of this variant in a case with an alternate molecular basis for disease was identified. BP5 requires the variant to be found in a case with a clear alternate genetic cause.
BP6 Not met ClinVar classification includes 4 clinical laboratories reporting 'Likely benign,' but the review status is 'criteria provided, single submitter' (1-star). No expert panel (3-star) classification as benign or likely benign exists. The BP6 threshold requiring a reputable source to classify as benign is not met.
clinvar
BP7 N/A NM_032043.3:c.736A>G (p.Ile246Val) is a missense variant, not a synonymous variant. BP7 is only applicable to synonymous variants without predicted splice impact.
PM3 N/A This variant is being assessed for a dominant disorder framework; PM3 (in trans with a pathogenic variant for recessive disorders) is not applicable.
PM4 N/A This variant is a substitution (missense), not a protein-length-altering change (in-frame deletion/insertion or stop-loss).
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