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BRIP1c.1372G>CUncertain significance
Print report
Variant interpretation report

BRIP1 c.1372G>C, p.(Glu458Gln)

NM_032043.3:c.1372G>C NP_114432.2:p.(Glu458Gln) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

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

Uncertain.The recorded classification is uncertain significance.

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: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

NM_032043.3:c.1372G>C is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, indicating it is not present in large population cohorts. Allele frequency is below the 0.1% threshold for PM2 application.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple lines of computational evidence suggest no deleterious impact. REVEL score is 0.334, BayesDel score is -0.138785 (negative/benign-leaning), and SpliceAI max delta score is 0.01 (no splicing impact). No computational tool predicts a pathogenic effect.

Recorded classification: Uncertain significance

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, BP4 supporting; combination = 1 supporting + 1 supporting benign, which maps to VUS.

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
0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions

2 Uncertain significance. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

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: 2 met · 12 not met · 0 not assessed · 13 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

NM_032043.3:c.1372G>C (p.Glu458Gln) is a missense variant in exon 10 of BRIP1.

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, consistent with PM2 (supporting).

Multiple computational tools predict no deleterious effect: REVEL score 0.334, BayesDel score -0.138785, and SpliceAI max delta 0.01, supporting BP4 (supporting).

No well-established functional studies have been performed for this variant; OncoKB reports unknown oncogenic effect (PS3 and BS3 not met).

ClinVar classifies this variant as Uncertain significance based on 2 clinical laboratory submissions (PS4, PP5 not met).

No segregation data, de novo observations, case-control studies, or variant-specific publications were identified for this variant.

This variant does not qualify as a null variant per ClinGen SVI PVS1 recommendations; PVS1 is not applicable.

The evidence yields PM2 (supporting) and BP4 (supporting), which effectively cancel each other. Based on the ACMG/AMP 2015 framework, this variant is classified as Uncertain significance.

Met · 2

PM2 SupportingNM_032043.3:c.1372G>C is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, indicating it is not present in large population cohorts. Allele frequency is below the 0.1% threshold for PM2 application. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes).
  • Absent from gnomAD v4.1 (exomes/genomes).
  • Absent from gnomAD-Canada v1.0 (genomes).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple lines of computational evidence suggest no deleterious impact. REVEL score is 0.334, BayesDel score is -0.138785 (negative/benign-leaning), and SpliceAI max delta score is 0.01 (no splicing impact). No computational tool predicts a pathogenic effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.334 (sub-pathogenic).
  • BayesDel: -0.138785 (benign-leaning).
  • SpliceAI max delta: 0.01 (no predicted splicing impact).
Sources
revelbayesdelspliceai ↗

Not met · 12 · evaluated, threshold not reached

PS3 No well-established in vitro or in vivo functional studies have been performed for NM_032043.3:c.1372G>C (p.Glu458Gln). OncoKB reports unknown oncogenic effect with no variant-specific functional evidence. REVEL score of 0.334 is inconclusive. Details ▾Hide ▴
Evidence considered
  • OncoKB classification: Unknown Oncogenic Effect
  • no variant-specific functional evidence curated.
  • REVEL score 0.334 does not independently establish pathogenic functional impact.
Still missing
  • No functional assay data available for this variant.
Sources
oncokb ↗revel
PS4 Variant has been observed in ClinVar as Uncertain significance (2 clinical laboratories) but no case-control data or statistically significant enrichment in affected individuals is available. PMID:25394175 is a general cancer referral guideline, not a variant-specific case-control study. Details ▾Hide ▴
Evidence considered
  • ClinVar: 2 clinical laboratory submissions
  • both VUS
  • no expert panel classification.
  • No case-control or cohort enrichment data identified.
Still missing
  • Absence of case-control data for this variant.
Sources
clinvar ↗
PP2 While loss-of-function is a known disease mechanism in BRIP1, insufficient evidence exists that missense variants are a predominant mechanism of disease in this gene with a low rate of benign missense variation. No gene-specific missense constraint metric (e.g., missense Z-score) is available to support PP2. Details ▾Hide ▴
Evidence considered
  • BRIP1 disease mechanism includes loss-of-function
  • but pathogenic missense variants also occur
  • no missense constraint data available.
Still missing
  • No BRIP1-specific missense constraint metric.
Sources
pvs1_gene_context
PP3 Multiple computational tools do not support a deleterious effect. REVEL score is 0.334 (below the pathogenic threshold of 0.5). BayesDel score is -0.138785 (benign-leaning). SpliceAI max delta is 0.01 (no predicted splicing impact). The Ambry Genetics ClinVar submission notes: 'in silico prediction for this alteration is inconclusive.' Details ▾Hide ▴
Evidence considered
  • REVEL: 0.334 (below pathogenic threshold).
  • BayesDel: -0.138785 (negative/benign-leaning).
  • SpliceAI max delta: 0.01 (no splicing impact).
  • Ambry submission notes inconclusive in silico prediction.
Sources
revelbayesdelspliceai ↗clinvar ↗
PP5 ClinVar classification is Uncertain significance (2 clinical laboratories, criteria provided, single submitter), not a pathogenic classification from a reputable source. PMID:25394175 is a general cancer predisposition referral guideline and does not discuss NM_032043.3:c.1372G>C specifically. Details ▾Hide ▴
Evidence considered
  • ClinVar VUS classification from 2 clinical laboratories
  • no pathogenic assertion from a reputable source.
  • PMID:25394175 is a practice guideline
  • not variant-specific.
Sources
clinvar ↗
BA1 Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is well below the 1% threshold required for BA1. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD (AF = 0)
  • far below BA1 threshold of >1%.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 Variant is absent from gnomAD. Allele frequency is not >0.3%, the threshold for BS1. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD
  • AF = 0
  • not >0.3%.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 No evidence of homozygous occurrence or co-occurrence with a pathogenic variant in trans in a recessive gene. Details ▾Hide ▴
Evidence considered
  • No homozygotes observed in gnomAD.
  • No trans co-occurrence data available.
Still missing
  • No data on co-occurrence with pathogenic variants in trans.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No well-established in vitro or in vivo functional studies have been performed demonstrating no deleterious effect of NM_032043.3:c.1372G>C (p.Glu458Gln). OncoKB reports unknown oncogenic effect with no variant-specific functional annotation. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no functional studies annotated for this variant.
Still missing
  • No functional assay data demonstrating a benign effect.
Sources
oncokb ↗
BS4 No segregation data available to demonstrate lack of co-segregation with disease. Details ▾Hide ▴
Evidence considered
  • No family segregation studies identified.
Still missing
  • No co-segregation data.
BP1 While loss-of-function is a known disease mechanism in BRIP1 (associated with Fanconi anemia and hereditary breast/ovarian cancer), pathogenic missense variants have been reported in this gene. Cannot conclude that only truncating variants cause disease in BRIP1, which is required for BP1 application. Details ▾Hide ▴
Evidence considered
  • BRIP1 LoF mechanism supported but missense variants also reported as pathogenic in ClinVar
  • gene is not a 'truncating-only' disease gene.
Sources
pvs1_gene_context
BP6 This variant is not reported as benign or likely benign by a reputable source. ClinVar classification is Uncertain significance. Details ▾Hide ▴
Evidence considered
  • ClinVar classification: VUS
  • no reputable source reports as benign.
Sources
clinvar ↗
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense variant p.Glu458Gln does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). PVS1 variant assessment confirms 'other' bucket; generic PVS1 framework is not applicable. Details ▾Hide ▴
Evidence considered
  • NM_032043.3:c.1372G>C is a missense variant (p.Glu458Gln) in exon 10
  • not a predicted null variant.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS1 N/ANo known pathogenic variant at the same amino acid residue (E458) with a different missense change has been identified in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search found zero same-residue comparator variants
  • no PS1-relevant pathogenic variant at Glu458.
Sources
pm5_candidates
PS2 N/ANo de novo observation confirmed for NM_032043.3:c.1372G>C. Details ▾Hide ▴
Evidence considered
  • No de novo report identified in ClinVar or literature.
PM1 N/AVariant does not lie in a statistically significant mutational hotspot. Cancer Hotspots analysis is negative, and no critical functional domain without benign variation has been identified at this residue. Details ▾Hide ▴
Evidence considered
  • Hotspot analysis negative for statistical significance
  • residue not in a known critical domain lacking benign variation.
PM5 N/ANo pathogenic comparator variant at the same amino acid residue (Glu458) identified. PM5 candidate search returned zero same-residue candidates. Details ▾Hide ▴
Evidence considered
  • Zero same-residue candidate variants found in ClinVar
  • no pathogenic comparator at E458 available for PM5.
Sources
pm5_candidates
PM6 N/ANo confirmed de novo observation for NM_032043.3:c.1372G>C with confirmed parentage. Details ▾Hide ▴
Evidence considered
  • No de novo report identified in ClinVar or the literature.
PP1 N/ANo co-segregation data available for this variant. Details ▾Hide ▴
Evidence considered
  • No family segregation studies identified.
Still missing
  • No co-segregation data.
PP4 N/ANo patient phenotype data provided for this case; cannot assess whether the phenotype is specific for BRIP1-related disease. Details ▾Hide ▴
Evidence considered
  • No patient phenotype or clinical data available in this case.
Still missing
  • Patient phenotype information not provided.
BP2 N/ANo observation of this variant in trans with a known pathogenic variant in a dominant gene, or in cis with a known pathogenic variant. Details ▾Hide ▴
Evidence considered
  • No data on allelic phase with other BRIP1 variants.
BP3 N/AMissense variant, not an in-frame deletion or insertion in a non-repeat region. Details ▾Hide ▴
Evidence considered
  • NM_032043.3:c.1372G>C is a substitution
  • not an in-frame indel.
BP5 N/ANo alternative molecular basis for disease has been identified in this case. Details ▾Hide ▴
Evidence considered
  • No alternative molecular diagnosis data provided.
BP7 N/AMissense variant NM_032043.3:c.1372G>C (p.Glu458Gln), not synonymous. BP7 is reserved for synonymous variants with no predicted splicing impact. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • not synonymous
  • BP7 does not apply.
PS5 N/ANot a de novo variant with confirmed maternity and paternity; this criterion is reserved for established de novo observations. Details ▾Hide ▴
Evidence considered
  • No de novo report identified.

Identifiers

Gene
BRIP1
Transcript
NM_032043.3
Coding (HGVS c.)
NM_032043.3:c.1372G>C
Protein (HGVS p.)
NP_114432.2:p.(Glu458Gln)
GRCh38
chr17:61793698 C>G
GRCh37
chr17:59871059 C>G
ClinVar
630785

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 +380 bp
0.000
SpliceAI acceptor gainat +31 bp
0.010
SpliceAI donor lossat -69 bp
0.000
SpliceAI donor gainat -101 bp
0.010
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.010

Other predictors

REVEL
0.334
BayesDel
-0.139

How the predictions were used

BP4 SupportingMultiple lines of computational evidence suggest no deleterious impact. REVEL score is 0.334, BayesDel score is -0.138785 (negative/benign-leaning), and SpliceAI max delta score is 0.01 (no splicing impact). No computational tool predicts a pathogenic effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.334 (sub-pathogenic).
  • BayesDel: -0.138785 (benign-leaning).
  • SpliceAI max delta: 0.01 (no predicted splicing impact).
Sources
revelbayesdelspliceai ↗
PP3 Multiple computational tools do not support a deleterious effect. REVEL score is 0.334 (below the pathogenic threshold of 0.5). BayesDel score is -0.138785 (benign-leaning). SpliceAI max delta is 0.01 (no predicted splicing impact). The Ambry Genetics ClinVar submission notes: 'in silico prediction for this alteration is inconclusive.' Details ▾Hide ▴
Evidence considered
  • REVEL: 0.334 (below pathogenic threshold).
  • BayesDel: -0.138785 (negative/benign-leaning).
  • SpliceAI max delta: 0.01 (no splicing impact).
  • Ambry submission notes inconclusive in silico prediction.
Sources
revelbayesdelspliceai ↗clinvar ↗
BP7 N/AMissense variant NM_032043.3:c.1372G>C (p.Glu458Gln), not synonymous. BP7 is reserved for synonymous variants with no predicted splicing impact. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • not synonymous
  • BP7 does not apply.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.334. BayesDel score = -0.138785.

2 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • 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.
    Richards S et al. · 2015
    ACMG/AMP standards and guidelines for the interpretation of sequence variants. This is a methodological framework paper and does not discuss NM_032043.3:c.1372G>C or BRIP1 specifically.
    Does not name this variant
    PMID 25741868 ↗
  • A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
    Hampel H et al. · 2015
    ACMG/NSGC practice guideline on referral indications for cancer predisposition assessment. Discusses general referral criteria for cancer genetic counseling and does not discuss NM_032043.3:c.1372G>C or any BRIP1-specific variants.
    Does not name this variant
    PMID 25394175 ↗

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 0.010 Open source ↗
ClinVar 2 Uncertain significance 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 has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 630785)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.334. BayesDel score = -0.138785.

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.