NM_032043.3:c.476A>C

BRIP1 · NP_114432.2:p.(Lys159Thr) · NM_032043.3

GRCh37: chr17:59926521 T>G · GRCh38: chr17:61849160 T>G

Gene: BRIP1 Transcript: NM_032043.3

Final call

Likely Benign

PM2 supporting BP1 supporting benign BP4 supporting benign

Variant details

Gene

BRIP1

Transcript

NM_032043.3

Protein

NP_114432.2:p.(Lys159Thr)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

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.

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).

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

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	This is a missense variant (p.Lys159Thr); it does not fall into any generic PVS1 null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus) per ClinGen SVI PVS1 framework (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No known pathogenic variant with the identical amino acid change (p.Lys159Thr) has been identified in ClinVar or the literature. PS1 requires a previously established pathogenic variant at the same residue with the same amino acid substitution.	clinvar
PS2	Not met	No de novo observation with confirmed paternity and maternity was identified for this variant. PS2 requires a de novo event with both parental relationships confirmed.
PS3	Not met	No well-established in vitro or in vivo functional studies supportive of a damaging effect were identified for this variant. OncoKB classifies the variant as having unknown oncogenic effect with no variant-specific functional evidence.	oncokb
PS4	Not met	No case-control or cohort data demonstrating statistically significant enrichment of this variant in affected individuals versus controls were identified. The variant is absent from all population databases and has no reported prevalence in affected cohorts.
PS5	Not met	No alternative pathogenic variant at the same nucleotide position with a different substitution was identified. PS5 requires a different nucleotide change at the same position that is established as pathogenic.
PM1	Not met	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. Residue p.Lys159 is outside the DEAH helicase core domain.
PM2	Met	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%).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No missense variant at the same amino acid residue (p.Lys159) with an established pathogenic classification was identified. Automated PM5 candidate harvesting returned zero same-residue candidates.	pm5_candidates
PM6	Not met	No de novo observation was identified for this variant. PM6 requires a de novo finding without confirmation of paternity and maternity.
PP1	Not met	No co-segregation data in affected family members was identified. PP1 requires the variant to co-segregate with disease in multiple affected family members.
PP2	Not assessed	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. BRIP1 is a known cancer predisposition gene, but no gene-specific missense constraint metrics (Z-score, pLI, missense o/e) were available in the evidence packet to support or refute PP2.
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.311 (below typical pathogenic threshold of 0.5), BayesDel score is 0.027 (strongly benign-leaning), and SpliceAI predicts no splicing impact (max delta 0.05). The ensemble of in silico predictions does not reach the threshold for PP3.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history data were available. PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology.
PP5	Not met	No reputable source has recently reported this variant as pathogenic. The variant is absent from ClinVar and no publications mention it.	clinvar
BA1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is 0%, well below the BA1 threshold (>1% for non-VCEP generic ACMG).	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from all population databases (gnomAD v2.1, v4.1, Canada). The observed allele frequency of 0% does not exceed the BS1 threshold (>0.3% for non-VCEP generic ACMG).	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No observation of this variant in a homozygous state in healthy adults was identified. BS2 requires observation in trans with a pathogenic variant (for dominant disorders) or in homozygous state in unaffected individuals.
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing were identified. BS3 requires functional evidence conclusively showing no pathogenic effect.
BS4	Not met	No lack of segregation in affected family members was identified. BS4 requires observation of the variant in a healthy family member who is non-segregating with disease.
BP1	Met	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.	pvs1_gene_context pvs1_generic_framework
BP2	Not met	No phase data were available. BP2 requires observation in trans with a pathogenic variant (for fully penetrant dominant disorders) or in cis with a pathogenic variant.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions without known function. This is a single-nucleotide substitution, not an in-frame indel.
BP4	Met	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 bayesdel spliceai
BP5	Not met	No data were available indicating an alternate molecular basis for disease in a patient carrying this variant. BP5 requires identification of a different causal variant explaining the phenotype.
BP6	Not met	No reputable source has reported this variant as benign or likely benign. The variant is absent from ClinVar, and no benign assertion exists in the literature.	clinvar
BP7	N/A	BP7 is specific to synonymous (silent) variants with no predicted splice impact and low nucleotide conservation. This is a missense variant (c.476A>C, p.Lys159Thr), not a synonymous variant.

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