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BRIP1c.1171A>GUncertain significance
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Variant interpretation report

BRIP1 c.1171A>G, p.(Ile391Val)

NM_032043.3:c.1171A>G NP_114432.2:p.(Ile391Val) 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
PM2Moderate
PM2 · moderate

This variant is very rare in population databases. In gnomAD v2.1 the allele frequency is 3.99431e-06 (1/250356), and in gnomAD v4.1 the allele frequency is 4.95952e-06 (8/1613060) with grpmax FAF 3.472e-05; all are well below the 0.1% PM2 threshold.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple computational findings support no meaningful impact. SpliceAI predicts no significant splice effect with a maximum delta score of 0.00, REVEL is 0.156, and BayesDel is -0.370746, which together support a benign computational interpretation rather than a damaging one.

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 moderate, BP4 supporting benign; combination = 1 moderate, which maps to VUS because the evidence is conflicting.

02The sources

Evidence at a glance

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

gnomAD v4.1
gnomAD v2.1
Population frequency
8 / 1,613,060 alleles

gnomAD v4.1: 8 / 1,613,060 alleles. Recorded AF 4.95952e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.99431e-06; MAF= 0.00040%, 1/250356 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.84815e-06; MAF= 0.00088%, 1/113018 alleles, homozygotes = 0).

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗
No screenshot for this evidence
Computational predictions
Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

Applied · BP4 →
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
Not assessed

No COSMIC evidence statement is recorded in this case.

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.

28 criteria with recorded statuses: 2 met · 4 not met · 18 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

The BRIP1 c.1171A>G (p.Ile391Val) variant has been reported in ClinVar and is currently classified there as a variant of uncertain significance with single-submitter review status.

This variant is very rare in population databases, with gnomAD v2.1 AF 3.99431e-06 (1/250356) and gnomAD v4.1 AF 4.95952e-06 (8/1613060), which are below the 0.1% PM2 threshold.

Computational data do not support a damaging effect: SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, REVEL is 0.156, and BayesDel is -0.370746.

Met · 2

PM2 ModerateThis variant is very rare in population databases. In gnomAD v2.1 the allele frequency is 3.99431e-06 (1/250356), and in gnomAD v4.1 the allele frequency is 4.95952e-06 (8/1613060) with grpmax FAF 3.472e-05; all are well below the 0.1% PM2 threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 total AF 3.99431e-06.
  • gnomAD v4.1 total AF 4.95952e-06 and grpmax FAF 3.472e-05.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 SupportingMultiple computational findings support no meaningful impact. SpliceAI predicts no significant splice effect with a maximum delta score of 0.00, REVEL is 0.156, and BayesDel is -0.370746, which together support a benign computational interpretation rather than a damaging one. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.00.
  • REVEL score 0.156.
  • BayesDel score -0.370746.
Sources
spliceai ↗revelbayesdel

Not met · 4 · evaluated, threshold not reached

PM1 This variant does not lie in a statistically significant hotspot, and no evidence was identified that codon 391 is a well-established critical functional region without benign variation. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots review found no hotspot row for BRIP1 Ile391.
Still missing
  • Need residue-level evidence showing codon 391 is a critical constrained site if PM1 is to be reconsidered.
Sources
hotspots ↗
PP3 Available computational evidence does not support a damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, REVEL is 0.156, and BayesDel is -0.370746, which do not support pathogenic computational evidence for this missense change. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.00.
  • REVEL score 0.156.
  • BayesDel score -0.370746.
Sources
spliceai ↗revelbayesdel
BA1 Population frequency does not meet the benign stand-alone threshold. The highest observed population value in the reviewed gnomAD data is far below the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 total AF 3.99431e-06.
  • gnomAD v4.1 total AF 4.95952e-06
  • highest reported population AF 8.01047e-05.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 Population frequency does not reach the benign strong threshold. The highest observed population frequency in the reviewed gnomAD data is 8.01047e-05 in gnomAD v4.1, which is well below the 0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 highest reported population AF 8.01047e-05.
  • gnomAD v2.1 highest reported population AF 8.84815e-06.
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 18 · no assessment recorded

PS1 No evidence was identified that a different nucleotide change producing the same amino acid substitution, p.(Ile391Val), has already been established as pathogenic or likely pathogenic. Details ▾Hide ▴
Still missing
  • Need same-amino-acid pathogenic comparison data.
PS2 No confirmed de novo occurrence with established maternity and paternity was identified for this variant. Details ▾Hide ▴
Still missing
  • Need patient-level inheritance data documenting a proven de novo event.
PS3 No well-established functional study showing a damaging effect of this specific variant was identified. Details ▾Hide ▴
Evidence considered
  • No variant-specific reviewed functional evidence was identified in the curated OncoKB result.
Still missing
  • Need a validated functional assay with direct p.(Ile391Val) results.
Sources
oncokb ↗
PS4 This variant is reported in ClinVar, but available evidence does not provide exact case counts, case-control enrichment, or a statistically increased prevalence in affected individuals compared with controls. Details ▾Hide ▴
Evidence considered
  • ClinVar lists the variant as uncertain significance with single-submitter review status.
Still missing
  • Need exact affected-case observations or case-control data for c.1171A>G.
Sources
clinvar ↗
PM3 No evidence was identified that this variant was observed in trans with a pathogenic variant in a recessive disease context. Details ▾Hide ▴
Still missing
  • Need phase-confirmed trans observations in an appropriate recessive context.
PM5 No evidence was identified that another missense change at codon 391 has been established as pathogenic or likely pathogenic. Details ▾Hide ▴
Still missing
  • Need codon-matched pathogenic missense comparison data.
PM6 No presumed de novo occurrence was identified for this variant. Details ▾Hide ▴
Still missing
  • Need case-level inheritance data showing a de novo event without full parental confirmation.
PP1 No segregation data were identified for this variant in affected relatives. Details ▾Hide ▴
Still missing
  • Need family segregation data with informative meioses.
PP2 Available evidence does not establish that BRIP1 is a gene in which pathogenic missense variation is a common mechanism and benign missense variation is uncommon for this specific ACMG criterion. Details ▾Hide ▴
Still missing
  • Need gene-level missense constraint and mechanism evidence supporting PP2 use.
PP4 No highly specific phenotype or family history attributable to this exact variant was identified. Details ▾Hide ▴
Still missing
  • Need phenotype data showing a presentation highly specific for BRIP1-related disease.
PP5 ClinVar lists this variant as uncertain significance with single-submitter review status, which does not provide a qualifying pathogenic reputable-source assertion for PP5. Details ▾Hide ▴
Evidence considered
  • ClinVar classification: uncertain significance
  • review status: criteria provided
  • single submitter.
Still missing
  • Need an independent qualifying pathogenic reputable-source assertion if PP5 were to be considered.
Sources
clinvar ↗
BS2 No evidence was identified showing this variant in healthy adult individuals in a manner sufficient for BS2 assessment. Details ▾Hide ▴
Still missing
  • Need phenotype-qualified healthy adult observations or gene-specific BS2 guidance.
BS3 No well-established functional study showing normal protein function for this specific variant was identified. Details ▾Hide ▴
Evidence considered
  • No variant-specific reviewed functional evidence was identified in the curated OncoKB result.
Still missing
  • Need a validated benign functional assay with direct p.(Ile391Val) results.
Sources
oncokb ↗
BS4 No non-segregation data were identified for this variant. Details ▾Hide ▴
Still missing
  • Need informative family data showing lack of segregation with disease.
BP1 This is a missense variant, but available evidence in the reviewed materials does not establish that BRIP1 disease is caused predominantly by truncating variants to the extent required for BP1 application. Details ▾Hide ▴
Evidence considered
  • Gene-level evidence supports loss of function as a mechanism
  • but BP1-specific missense-mechanism exclusion was not established.
Still missing
  • Need gene-specific evidence showing pathogenic missense variants are not a common disease mechanism.
Sources
pvs1_gene_context
BP2 No evidence was identified that this variant occurs in trans with a pathogenic variant for a dominant disorder, or in cis with a pathogenic variant in a way that supports BP2. Details ▾Hide ▴
Still missing
  • Need phase and co-occurrence data.
BP5 No alternate molecular explanation was identified that would make this variant an incidental finding in the evaluated disease context. Details ▾Hide ▴
Still missing
  • Need case-level phenotype and alternate-cause data if BP5 is to be considered.
BP6 No qualifying benign reputable-source assertion was identified. ClinVar reports this variant as uncertain significance rather than benign or likely benign. Details ▾Hide ▴
Evidence considered
  • ClinVar classification: uncertain significance.
Still missing
  • Need an independent qualifying benign reputable-source assertion if BP6 were to be considered.
Sources
clinvar ↗
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense substitution, and the generic PVS1 assessment does not place it in a null-variant category such as nonsense, frameshift, or canonical +/-1,2 splice-site change. Although BRIP1 loss of function is an established disease mechanism, available evidence does not support applying PVS1 to c.1171A>G. Details ▾Hide ▴
Evidence considered
  • BRIP1 loss-of-function mechanism is supported at the gene level.
  • Variant-level PVS1 scaffold indicates this missense change is outside default generic PVS1 null-variant buckets.
Still missing
  • RNA data would be needed to reconsider PVS1 if an abnormal splicing effect were demonstrated.
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗
PM4 N/AThis is not a protein length-changing variant such as an in-frame insertion, in-frame deletion, or stop-loss variant. Details ▾Hide ▴

No further detail was recorded.

BP3 N/AThis is not an in-frame insertion or deletion in a repetitive region. Details ▾Hide ▴

No further detail was recorded.

BP7 N/AThis is a missense variant, not a synonymous or deep intronic change, so BP7 does not apply. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
BRIP1
Transcript
NM_032043.3
Coding (HGVS c.)
NM_032043.3:c.1171A>G
Protein (HGVS p.)
NP_114432.2:p.(Ile391Val)
GRCh38
chr17:61799269 T>C
GRCh37
chr17:59876630 T>C

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 8 / 1,613,060 alleles AF 4.96e-06 · 0 homozygotes · FAF 3.47e-05
gnomAD v2.1 1 / 250,356 alleles AF 3.99e-06 · 0 homozygotes

By genetic ancestry

gnomAD v4.1

AF 5e-06 · 8 / 1,613,060 alleles · 0 hom · FAF 3.5e-05
African/African American6 / 74,902 8e-05
European (non-Finnish)2 / 1,179,352 1.7e-06
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.

gnomAD v2.1

AF 4e-06 · 1 / 250,356 alleles · 0 hom
European (non-Finnish)1 / 113,018 8.8e-06
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 4.95952e-06; MAF= 0.00050%, 8/1613060 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 8.01047e-05; MAF= 0.00801%, 6/74902 alleles, homozygotes = 0); grpmax FAF= 3.472e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.99431e-06; MAF= 0.00040%, 1/250356 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.84815e-06; MAF= 0.00088%, 1/113018 alleles, homozygotes = 0).

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP4 SupportingMultiple computational findings support no meaningful impact. SpliceAI predicts no significant splice effect with a maximum delta score of 0.00, REVEL is 0.156, and BayesDel is -0.370746, which together support a benign computational interpretation rather than a damaging one. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.00.
  • REVEL score 0.156.
  • BayesDel score -0.370746.
Sources
spliceai ↗revelbayesdel
PP3 Available computational evidence does not support a damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, REVEL is 0.156, and BayesDel is -0.370746, which do not support pathogenic computational evidence for this missense change. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.00.
  • REVEL score 0.156.
  • BayesDel score -0.370746.
Sources
spliceai ↗revelbayesdel
BP7 N/AThis is a missense variant, not a synonymous or deep intronic change, so BP7 does not apply. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.156. BayesDel score = -0.370746.

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 8 / 1,613,060 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Captured SpliceAI source record 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

This variant is present in gnomAD v4.1 (AF= 4.95952e-06; MAF= 0.00050%, 8/1613060 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 8.01047e-05; MAF= 0.00801%, 6/74902 alleles, homozygotes = 0); grpmax FAF= 3.472e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.99431e-06; MAF= 0.00040%, 1/250356 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.84815e-06; MAF= 0.00088%, 1/113018 alleles, homozygotes = 0).

ClinVar

This variant has been reported in ClinVar as Uncertain significance (8 clinical laboratories).

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.156. BayesDel score = -0.370746.

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.