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BRIP1c.476A>CLikely benign
Print report
Variant interpretation report

BRIP1 c.476A>C, p.(Lys159Thr)

NM_032043.3:c.476A>C NP_114432.2:p.(Lys159Thr) View identifiers
Classification
Likely benign

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.

Likely benign.A likely benign classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About BRIP1

No gene-level summary was recorded for this case.

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.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 2
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

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%).

Benign criteria applied · 2
BP1Supporting
BP1 · supporting

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.

BP4Supporting
BP4 · supporting

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.

Recorded classification: Likely benign

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.050 maximum delta

Recorded SpliceAI maximum delta score: 0.050. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

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.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

27 criteria with recorded statuses: 3 met · 20 not met · 1 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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).

Met · 3

PM2 SupportingThis 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%). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes).
  • Absent from gnomAD v4.1 (exomes/genomes).
  • Absent from gnomAD-Canada v1.0 (HostSeq genomes).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP1 SupportingBRIP1 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. Details ▾Hide ▴
Evidence considered
  • BRIP1 loss of function is the established germline disease mechanism (Fanconi anemia
  • hereditary breast/ovarian cancer).
  • Supporting literature (PMID:41070818) confirms BRIP1 as a moderate-penetrance cancer predisposition gene where pathogenic variants are predominantly truncating.
  • This variant is a missense substitution
  • not a truncating/nonsense/frameshift variant.
Sources
pvs1_gene_contextpvs1_generic_framework ↗
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.311 (below pathogenic threshold).
  • BayesDel: 0.027 (benign-leaning prediction).
  • SpliceAI: max delta 0.05 (no predicted splice impact).
Sources
revelbayesdelspliceai ↗

Not met · 20 · evaluated, threshold not reached

PS1 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. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar. No same-change pathogenic comparator exists at this residue.
Sources
clinvar ↗
PS2 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. Details ▾Hide ▴
Evidence considered
  • No de novo data available in any evidence source.
Still missing
  • No parental testing data or de novo reports available.
PS3 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. Details ▾Hide ▴
Evidence considered
  • OncoKB reports unknown oncogenic effect
  • no variant-specific functional studies identified. No PMIDs with functional data for this variant.
Still missing
  • No functional assay data available for p.Lys159Thr.
Sources
oncokb ↗
PS4 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. Details ▾Hide ▴
Evidence considered
  • Variant not observed in any case or control cohort. No published prevalence data available.
Still missing
  • No case-control or cohort data available.
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. Residue p.Lys159 is outside the DEAH helicase core domain. Details ▾Hide ▴
Evidence considered
  • CancerHotspots: not a significant hotspot residue. No domain-level constraint data suggesting critical functional region.
PM5 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. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search returned 0 same-residue candidates in ClinVar. No pathogenic comparator at p.Lys159.
Sources
pm5_candidates
PM6 No de novo observation was identified for this variant. PM6 requires a de novo finding without confirmation of paternity and maternity. Details ▾Hide ▴
Evidence considered
  • No de novo reports available in any evidence source.
Still missing
  • No de novo data or parental testing available.
PP1 No co-segregation data in affected family members was identified. PP1 requires the variant to co-segregate with disease in multiple affected family members. Details ▾Hide ▴
Evidence considered
  • No family studies or segregation data available.
Still missing
  • No segregation or family data available.
PP3 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. Details ▾Hide ▴
Evidence considered
  • REVEL score: 0.311 (below pathogenic threshold of 0.5).
  • BayesDel score: 0.027 (benign-leaning
  • well below typical pathogenic threshold).
  • SpliceAI max delta: 0.05 (no predicted splice alteration).
Sources
revelbayesdelspliceai ↗
PP4 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. Details ▾Hide ▴
Evidence considered
  • No clinical phenotype or family history data provided for assessment.
Still missing
  • Patient phenotype and family history not available for review.
PP5 No reputable source has recently reported this variant as pathogenic. The variant is absent from ClinVar and no publications mention it. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar. No recent publications or reputable source reports this variant as pathogenic.
Sources
clinvar ↗
BA1 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). Details ▾Hide ▴
Evidence considered
  • Allele frequency = 0.0 across all gnomAD datasets
  • far below the BA1 threshold of >1%.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 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). Details ▾Hide ▴
Evidence considered
  • Allele frequency = 0.0 across all gnomAD datasets. Does not meet BS1 threshold (>0.3%).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 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. Details ▾Hide ▴
Evidence considered
  • Variant absent from population databases
  • no homozygote or compound heterozygote data available.
BS3 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. Details ▾Hide ▴
Evidence considered
  • No functional studies available. OncoKB reports unknown oncogenic effect with no variant-specific data.
Still missing
  • No functional assay data available to demonstrate benign effect.
BS4 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. Details ▾Hide ▴
Evidence considered
  • No family segregation data available.
Still missing
  • No segregation data available.
BP2 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. Details ▾Hide ▴
Evidence considered
  • No phase or co-occurrence data available.
Still missing
  • No phase data available.
BP5 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. Details ▾Hide ▴
Evidence considered
  • No alternate molecular diagnosis or causal variant data available.
Still missing
  • No data on alternate molecular diagnoses.
BP6 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. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar. No benign/likely benign assertion from any reputable source.
Sources
clinvar ↗
PS5 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. Details ▾Hide ▴
Evidence considered
  • No nucleotide-level comparator variants at c.476 identified in ClinVar or databases.

Not assessed · 1 · no assessment recorded

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. 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. Details ▾Hide ▴
Evidence considered
  • No missense constraint metrics (Z-score
  • o/e ratio
  • or comparable) available for BRIP1 in evidence sources. HCI prior lookup returned no data for this gene.
Still missing
  • Missense constraint Z-score or o/e ratio needed from gnomAD for BRIP1.
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis 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). Details ▾Hide ▴
Evidence considered
  • Missense variant in exon 5
  • not a predicted null variant. The ClinGen SVI PVS1 decision tree does not apply to missense substitutions.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions without known function. This is a single-nucleotide substitution, not an in-frame indel. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 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. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
BRIP1
Transcript
NM_032043.3
Coding (HGVS c.)
NM_032043.3:c.476A>C
Protein (HGVS p.)
NP_114432.2:p.(Lys159Thr)
GRCh38
chr17:61849160 T>G
GRCh37
chr17:59926521 T>G

Gene diagram

Every interpreted variant in BRIP1, mapped onto the exon structure of NM_032043.3. Select a row to find it on the plot.

BRIP1NM_032043.3
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -31 bp
0.000
SpliceAI acceptor gainat +96 bp
0.050
SpliceAI donor lossat +138 bp
0.000
SpliceAI donor gainat -31 bp
0.020
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.060

Other predictors

REVEL
0.311
BayesDel
0.027

How the predictions were used

BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.311 (below pathogenic threshold).
  • BayesDel: 0.027 (benign-leaning prediction).
  • SpliceAI: max delta 0.05 (no predicted splice impact).
Sources
revelbayesdelspliceai ↗
PP3 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. Details ▾Hide ▴
Evidence considered
  • REVEL score: 0.311 (below pathogenic threshold of 0.5).
  • BayesDel score: 0.027 (benign-leaning
  • well below typical pathogenic threshold).
  • SpliceAI max delta: 0.05 (no predicted splice alteration).
Sources
revelbayesdelspliceai ↗
BP7 N/ABP7 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. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.311. BayesDel score = 0.0269509.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.050 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

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

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.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.