Classification rationale

PM2 BP1 VUS

BRIP1 c.1655T>C missense · exon 12

PM2 supporting: gnomAD v4.1 allele frequency is 5.5764e-05 with zero homozygotes. BP1 supporting: BRIP1 disease-causing variants are predominantly truncating, while this variant is missense.

PM2 + BP1 → VUS

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_032043.3 · variants mapped to exon structure

BRIP1 NM_032043.3

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 22 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 · 2

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

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 v4.1 reports 90/1,613,944 alleles, total AF 5.5764e-05, and zero homozygotes.gnomAD v2.1 reports 5/282,702 alleles, total AF 1.768646843672843e-05, and zero homozygotes.The supplied generic ClinGen SVI PM2 calibration is AF <=0.0001 at supporting strength; the threshold source supplied with the calibration is ACMG/AMP 2015 (PMID:25741868).

gnomad_v2 ↗gnomad_v4 ↗PMID:25741868 ↗

BP1 supporting Benign

Met at supporting strength: BRIP1 disease-causing mutations are predominantly truncating, while rare missense variants comprise only a small proportion.

The reviewed paper states that BRIP1 disease-causing mutations predominantly cause premature protein truncation or nonsense-mediated RNA decay, with only a small proportion of rare missense variants disrupting critical functions.The target variant is a missense substitution, NM_032043.3:c.1655T>C (NP_114432.2:p.Ile552Thr).

PMID:18163131 ↗

Assessed · not applied · 7 not met · 15 not assessed

Pathogenic

PS1 Not assessed: no independently established pathogenic variant with the same amino-acid change as p.Ile552Thr was identified.

PS2 Not assessed: no documented parental testing or confirmed de novo status is available for NM_032043.3:c.1655T>C.

PS3 Not assessed: no variant-specific validated functional assay or assay-control result is available for BRIP1 p.Ile552Thr.

PS4 Not assessed: no exact-variant case-control counts, odds ratio, confidence interval, or p-value are available to establish significant enrichment.

PM1 Not assessed: no BRIP1-approved domain table or validated critical-domain evidence establishes that residue 552 meets PM1.

PM3 Not assessed: no documented affected proband with a pathogenic BRIP1 allele in trans or phase-resolved biallelic genotype is available.

PM5 Not assessed: no different pathogenic missense variant at BRIP1 residue 552 was identified for comparison.

PM6 Not assessed: neither suspected de novo occurrence nor the required proband and family-history context is documented.

PP1 Not assessed: no affected relatives, informative meioses, or segregation count is reported for NM_032043.3:c.1655T>C.

PP2 Not met: BRIP1 disease-causing variants are described as predominantly truncating, with only a small proportion of rare missense variants.

PP3 Not met: missense REVEL score 0.607 is below the 0.644 supporting PP3 threshold.

PP4 Not assessed: reported cancer contexts are broad and lack a disease-specific phenotype sufficiently characteristic to support PP4.

PP5 Not met: exact-variant ClinVar has zero expert-panel submissions and reports only Uncertain significance laboratory assertions.

Benign

BA1 Not met: gnomAD v4.1 total allele frequency 5.5764e-05 is far below the generic BA1 threshold of 0.05.

BS1 Not met: gnomAD v4.1 total allele frequency 5.5764e-05 is below the supplied generic BS1 threshold of 0.01.

BS2 Not assessed: gnomAD reports zero homozygotes but does not establish healthy-adult status, age, penetrance, or qualifying phenotype information.

BS3 Not assessed: no variant-specific validated functional assay or assay-control result is available to demonstrate normal BRIP1 p.Ile552Thr function.

BS4 Not assessed: no adequately phenotyped, tested unaffected relatives are documented to evaluate non-segregation.

BP2 Not assessed: no phase-resolved observation places this variant in trans with a pathogenic allele or in cis with a pathogenic variant.

BP4 Not met: missense REVEL score 0.607 is above the 0.29 supporting BP4 threshold.

BP5 Not assessed: no documented alternative molecular diagnosis explains the relevant phenotype in a patient carrying this exact variant.

BP6 Not met: exact-variant ClinVar has zero expert-panel submissions and reports only Uncertain significance laboratory assertions.

N/A · 4 PVS1 · PM4 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 5.5764e-05; MAF= 0.00558%, 90/1613944 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.00012802; MAF= 0.01280%, 8/62490 alleles, homozygotes = 0); grpmax FAF= 5.71e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 1.76865e-05; MAF= 0.00177%, 5/282702 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 4.00705e-05; MAF= 0.00401%, 1/24956 alleles, homozygotes = 0); grpmax FAF= 7.01e-06.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0056% · 90 / 1,613,944
0 hom · FAF 0.0057%

Remaining individuals 8 / 62,490	0.013%
European (non-Finnish) 82 / 1,180,032	0.0069%

+ 8 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0018% · 5 / 282,702
0 hom · FAF 0.0007%

African/African American 1 / 24,956	0.004%
European (non-Finnish) 4 / 129,108	0.0031%

+ 6 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (12 clinical laboratories). (ClinVarID = 142965)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.607. BayesDel score = 0.0109582.

SpliceAI ↗

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.

OncoKB ↗

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.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

2papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 7 further PMIDs triaged but not cited — see Sources & references.

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

PMID 25741868 ↗ CLINVAR · functional

Found

the threshold source supplied with the calibration is ACMG/AMP 2015 (PMID:25741868).

Applied to

→PM2 supporting

Rule & framework references · cited for criterion definitions, not variant evidence

18163131 ↗ The emerging landscape of breast cancer susceptibility.

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 7 PMIDs not cited in assessment

26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR

26689913 ↗ Patterns and functional implications of rare germline variants across 12 cancer types. CLINVAR

28135145 ↗ Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. CLINVAR

34326862 ↗ Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach. CLINVAR

15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. CLINVAR

25980754 ↗ Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

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