Variant classification summary

NM_032043.3:c.1655T>C

BRIP1 · NP_114432.2:p.(Ile552Thr) · NM_032043.3

GRCh37: chr17:59858340 A>G · GRCh38: chr17:61780979 A>G

Gene: BRIP1 Transcript: NM_032043.3

Final call

VUS

PM2 supporting BP1 supporting

Variant details

Gene

BRIP1

Transcript

NM_032043.3

Protein

NP_114432.2:p.(Ile552Thr)

gnomAD AF

5.576401659537134e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supporting: gnomAD v4.1 allele frequency is 5.5764e-05 with zero homozygotes.

2

BP1 supporting: BRIP1 disease-causing variants are predominantly truncating, while this variant is missense.

Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting pathogenic criterion plus one supporting benign criterion does not meet a defined pathogenic, likely pathogenic, benign, or likely benign combination, so the result is VUS.

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	PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_032043.3:c.1655T>C in BRIP1 is a missense substitution predicted to produce NP_114432.2:p.(Ile552Thr). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no independently established pathogenic variant with the same amino-acid change as p.Ile552Thr was identified.
PS2	Not assessed	Not assessed: no documented parental testing or confirmed de novo status is available for NM_032043.3:c.1655T>C.
PS3	Not assessed	Not assessed: no variant-specific validated functional assay or assay-control result is available for BRIP1 p.Ile552Thr.	clinvar oncokb
PS4	Not assessed	Not assessed: no exact-variant case-control counts, odds ratio, confidence interval, or p-value are available to establish significant enrichment.	clinvar
PM1	Not assessed	Not assessed: no BRIP1-approved domain table or validated critical-domain evidence establishes that residue 552 meets PM1.
PM2	Met	Met at supporting strength: gnomAD v4.1 total allele frequency 5.5764e-05 is below the PM2 threshold of 0.0001, with zero homozygotes.	gnomad_v2 gnomad_v4 PMID:25741868
PM3	Not assessed	Not assessed: no documented affected proband with a pathogenic BRIP1 allele in trans or phase-resolved biallelic genotype is available.	clinvar PMID:18163131
PM4	N/A	PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_032043.3:c.1655T>C in BRIP1 is a missense substitution predicted to produce NP_114432.2:p.(Ile552Thr). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different pathogenic missense variant at BRIP1 residue 552 was identified for comparison.
PM6	Not assessed	Not assessed: neither suspected de novo occurrence nor the required proband and family-history context is documented.
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or segregation count is reported for NM_032043.3:c.1655T>C.
PP2	Not met	Not met: BRIP1 disease-causing variants are described as predominantly truncating, with only a small proportion of rare missense variants.	PMID:18163131
PP3	Not met	Not met: missense REVEL score 0.607 is below the 0.644 supporting PP3 threshold.	revel
PP4	Not assessed	Not assessed: reported cancer contexts are broad and lack a disease-specific phenotype sufficiently characteristic to support PP4.	clinvar
PP5	Not met	Not met: exact-variant ClinVar has zero expert-panel submissions and reports only Uncertain significance laboratory assertions.	clinvar
BA1	Not met	Not met: gnomAD v4.1 total allele frequency 5.5764e-05 is far below the generic BA1 threshold of 0.05.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Not met	Not met: gnomAD v4.1 total allele frequency 5.5764e-05 is below the supplied generic BS1 threshold of 0.01.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports zero homozygotes but does not establish healthy-adult status, age, penetrance, or qualifying phenotype information.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific validated functional assay or assay-control result is available to demonstrate normal BRIP1 p.Ile552Thr function.	clinvar oncokb
BS4	Not assessed	Not assessed: no adequately phenotyped, tested unaffected relatives are documented to evaluate non-segregation.
BP1	Met	Met at supporting strength: BRIP1 disease-causing mutations are predominantly truncating, while rare missense variants comprise only a small proportion.	PMID:18163131
BP2	Not assessed	Not assessed: no phase-resolved observation places this variant in trans with a pathogenic allele or in cis with a pathogenic variant.	clinvar PMID:25980754 PMID:26689913 PMID:28135145
BP3	N/A	BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_032043.3:c.1655T>C in BRIP1 is a missense substitution predicted to produce NP_114432.2:p.(Ile552Thr). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: missense REVEL score 0.607 is above the 0.29 supporting BP4 threshold.	revel
BP5	Not assessed	Not assessed: no documented alternative molecular diagnosis explains the relevant phenotype in a patient carrying this exact variant.
BP6	Not met	Not met: exact-variant ClinVar has zero expert-panel submissions and reports only Uncertain significance laboratory assertions.	clinvar
BP7	N/A	BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_032043.3:c.1655T>C in BRIP1 is a missense substitution predicted to produce NP_114432.2:p.(Ile552Thr). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules

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