About BRIP1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRIP1 c.3069C>T, p.(Leu1023=)
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.
Words with a dotted underline have a short definition. Hover or tap them.
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 present at low frequency in population databases. The highest observed population frequency is 0.06533% in gnomAD v2.1 South Asian samples and 0.04721% in gnomAD v4.1 South Asian samples, both below the default 0.1% PM2 threshold, which supports PM2 under the generic fallback framework.
Benign criteria applied · 1
BP7Supporting
BP7 · supporting
This is a synonymous BRIP1 variant, p.(Leu1023=), and available splicing prediction does not indicate a meaningful splice effect. SpliceAI shows a maximum delta score of 0.01, supporting no significant splice impact, which meets BP7.
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, BP7 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
135 / 1,614,036 alleles
gnomAD v4.1: 135 / 1,614,036 alleles. Recorded AF 8.36413e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000106072; MAF= 0.01061%, 30/282826 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000653253; MAF= 0.06533%, 20/30616 alleles, homozygotes = 0); grpmax FAF= 0.00043223.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).
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
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 · 6 not met · 13 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The BRIP1 c.3069C>T (p.Leu1023=, p.L1023=) variant has been reported in ClinVar predominantly as likely benign or benign.
This variant is present at low frequency in gnomAD, with overall allele frequencies of 0.01061% in v2.1 and 0.00836% in v4.1, and highest observed South Asian frequencies of 0.06533% and 0.04721%, respectively; these values are below the default 0.1% PM2 threshold and below the 0.3% BS1 and 1% BA1 benign thresholds.
This synonymous variant is predicted to have no significant splice effect, with a SpliceAI maximum delta score of 0.01, which supports BP7 and argues against PP3.
No criteria match.
Met · 2
PM2 ModerateThis variant is present at low frequency in population databases. The highest observed population frequency is 0.06533% in gnomAD v2.1 South Asian samples and 0.04721% in gnomAD v4.1 South Asian samples, both below the default 0.1% PM2 threshold, which supports PM2 under the generic fallback framework. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 South Asian AF 0.000653253 (20/30616)
- gnomAD v4.1 South Asian AF 0.000472133 (43/91076)
Sources
BP7 SupportingThis is a synonymous BRIP1 variant, p.(Leu1023=), and available splicing prediction does not indicate a meaningful splice effect. SpliceAI shows a maximum delta score of 0.01, supporting no significant splice impact, which meets BP7. Details ▾Hide ▴
Evidence considered
- Synonymous protein consequence p.(Leu1023=)
- SpliceAI max delta score 0.01
Sources
Not met · 6 · evaluated, threshold not reached
PM1 Available evidence does not support location in a well-established mutational hotspot or critical functional domain without benign variation. Cancer Hotspots did not identify a significant hotspot at residue L1023, and OncoKB did not show variant-specific oncogenic curation. Details ▾Hide ▴
Evidence considered
- No hotspot row found at BRIP1 L1023
- OncoKB classification: Unknown Oncogenic Effect and not variant-specific
Still missing
- Hotspot review was marked uncertain and may benefit from manual confirmation if this criterion becomes important.
Sources
PP3 Available computational evidence does not support a deleterious effect on splicing. SpliceAI shows a maximum delta score of 0.01, which is consistent with no significant splice impact, so PP3 is not met. Details ▾Hide ▴
PP5 No reputable source classification supporting pathogenicity was identified. ClinVar submissions for this variant are benign or likely benign, so PP5 is not met. Details ▾Hide ▴
Evidence considered
- ClinVar overall classification Likely benign with additional Benign submissions
Sources
BA1 Population frequency does not reach the standalone benign threshold. The highest observed population frequency is 0.06533% in gnomAD v2.1 and 0.04721% in gnomAD v4.1, both below the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 South Asian AF 0.000653253
- gnomAD v4.1 South Asian AF 0.000472133
Sources
BS1 Population frequency does not exceed the strong benign threshold. The highest observed population frequency is 0.06533% in gnomAD v2.1 and 0.04721% in gnomAD v4.1, both below the default 0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 South Asian AF 0.000653253
- gnomAD v4.1 South Asian AF 0.000472133
Sources
BP6 Although ClinVar reports this variant as benign or likely benign, those submissions are listed with criteria provided rather than as unsupported assertions from a reputable source, so BP6 was not applied. Details ▾Hide ▴
Not assessed · 13 · no assessment recorded
PS1 No evidence was identified showing that a different nucleotide change producing the same amino acid alteration has been established as pathogenic, so PS1 was not assessed. Details ▾Hide ▴
Still missing
- A validated pathogenic alternate nucleotide change causing the same amino acid outcome was not identified.
PS2 No confirmed de novo occurrence with verified parentage was identified, so PS2 was not assessed. Details ▾Hide ▴
Still missing
- No de novo case data with parental confirmation were identified.
PS3 No well-established functional studies demonstrating a damaging effect of this specific variant were identified, so PS3 was not assessed. Details ▾Hide ▴
PS4 No case-control or enrichment data were identified showing this variant is significantly more common in affected individuals than in controls, so PS4 was not assessed. Details ▾Hide ▴
Evidence considered
- ClinVar reports benign/likely benign submissions but no qualifying prevalence evidence for pathogenic enrichment
Still missing
- No statistically supported affected-versus-control enrichment data were identified.
Sources
PM3 No evidence was identified showing this variant in trans with a pathogenic variant for a recessive disorder, so PM3 was not assessed. Details ▾Hide ▴
Still missing
- No confirmed phase data or recessive case observations were identified.
PM6 No assumed de novo occurrence was identified, so PM6 was not assessed. Details ▾Hide ▴
Still missing
- No de novo case data were identified.
PP1 No segregation data were identified for this variant, so PP1 was not assessed. Details ▾Hide ▴
Still missing
- No family segregation studies were identified.
PP4 No phenotype or family history data sufficiently specific for a single genetic cause were identified for this variant, so PP4 was not assessed. Details ▾Hide ▴
Still missing
- No case-level phenotype specificity data were identified.
BS2 No evidence was identified showing this variant in healthy adult individuals in a way that is sufficient to apply BS2, so BS2 was not assessed. Details ▾Hide ▴
Still missing
- No phenotype-linked healthy adult observation dataset was identified for BS2 application.
BS3 No well-established functional studies demonstrating no damaging effect of this specific variant were identified, so BS3 was not assessed. Details ▾Hide ▴
Still missing
- No variant-specific benign functional assay data were identified.
Sources
BS4 No segregation studies showing lack of segregation with disease were identified, so BS4 was not assessed. Details ▾Hide ▴
Still missing
- No informative family segregation studies were identified.
BP2 No phase data showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant were identified, so BP2 was not assessed. Details ▾Hide ▴
Still missing
- No phase or co-occurrence data were identified.
BP5 No evidence was identified for an alternate molecular basis explaining disease in carriers of this variant, so BP5 was not assessed. Details ▾Hide ▴
Still missing
- No alternate established molecular diagnosis data were identified.
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ABRIP1 loss of function is an established germline disease mechanism, but c.3069C>T is a synonymous variant and does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice variants; therefore PVS1 is not applicable. Details ▾Hide ▴
Evidence considered
- BRIP1 loss-of-function mechanism supported at the gene level
- Variant is synonymous p.(Leu1023=) and not a canonical splice-site change
Sources
PM4 N/AThis is a synonymous variant and does not change protein length, so PM4 is not applicable. Details ▾Hide ▴
Evidence considered
- Protein consequence p.(Leu1023=)
PM5 N/APM5 applies to novel missense changes at an amino acid residue where a different pathogenic missense change is known. This variant is synonymous, so PM5 is not applicable. Details ▾Hide ▴
Evidence considered
- Protein consequence p.(Leu1023=)
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation and where missense variants are a common disease mechanism. This variant is synonymous, so PP2 is not applicable. Details ▾Hide ▴
Evidence considered
- Protein consequence p.(Leu1023=)
BP1 N/ABP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. This variant is synonymous, so BP1 is not applicable. Details ▾Hide ▴
Evidence considered
- Protein consequence p.(Leu1023=)
BP3 N/ABP3 applies to in-frame indels in repetitive regions without known function. This variant is synonymous, so BP3 is not applicable. Details ▾Hide ▴
Evidence considered
- Protein consequence p.(Leu1023=)
BP4 N/ABP4 is generally used for missense or other sequence changes with multiple computational predictors supporting no impact. For this synonymous variant, the splice prediction evidence is captured under BP7 instead. Details ▾Hide ▴
Identifiers
- Gene
- BRIP1
- Transcript
- NM_032043.3
- Coding (HGVS c.)
- NM_032043.3:c.3069C>T
- Protein (HGVS p.)
- NP_114432.2:p.(Leu1023=)
- GRCh38
- chr17:61683977 G>A
- GRCh37
- chr17:59761338 G>A
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…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in BRIP1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
135 / 1,614,036 alleles
AF 8.36e-05 · 0 homozygotes · FAF 0.00036
gnomAD v2.1
30 / 282,826 alleles
AF 0.000106 · 0 homozygotes · FAF 0.000432
By genetic ancestry
gnomAD v4.1
AF 8.4e-05 · 135 / 1,614,036 alleles · 0 hom · FAF 0.00036
| South Asian43 / 91,076 | 0.00047 |
| Remaining individuals10 / 62,498 | 0.00016 |
| European (non-Finnish)81 / 1,180,014 | 6.9e-05 |
| African/African American1 / 74,974 | 1.3e-05 |
0 alternate alleles recorded in 6 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish.
gnomAD v2.1
AF 0.00011 · 30 / 282,826 alleles · 0 hom · FAF 0.00043
| South Asian20 / 30,616 | 0.00065 |
| Remaining individuals1 / 7,222 | 0.00014 |
| European (non-Finnish)9 / 129,156 | 7e-05 |
0 alternate alleles recorded in 5 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish).
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 8.36413e-05; MAF= 0.00836%, 135/1614036 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000472133; MAF= 0.04721%, 43/91076 alleles, homozygotes = 0); grpmax FAF= 0.00035972.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000106072; MAF= 0.01061%, 30/282826 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000653253; MAF= 0.06533%, 20/30616 alleles, homozygotes = 0); grpmax FAF= 0.00043223.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP7 SupportingThis is a synonymous BRIP1 variant, p.(Leu1023=), and available splicing prediction does not indicate a meaningful splice effect. SpliceAI shows a maximum delta score of 0.01, supporting no significant splice impact, which meets BP7. Details ▾Hide ▴
Evidence considered
- Synonymous protein consequence p.(Leu1023=)
- SpliceAI max delta score 0.01
Sources
PP3 Available computational evidence does not support a deleterious effect on splicing. SpliceAI shows a maximum delta score of 0.01, which is consistent with no significant splice impact, so PP3 is not met. Details ▾Hide ▴
BP4 N/ABP4 is generally used for missense or other sequence changes with multiple computational predictors supporting no impact. For this synonymous variant, the splice prediction evidence is captured under BP7 instead. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
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
135 / 1,614,036 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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/182356/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-59761338-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-61683977-G-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_032043.3%3Ac.3069…
- OncoKB ↗www.oncokb.org/gene/BRIP1/L1023=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRIP1+c.3069C%3ET
- Cancer hotspots ↗www.cancerhotspots.org/
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= 8.36413e-05; MAF= 0.00836%, 135/1614036 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000472133; MAF= 0.04721%, 43/91076 alleles, homozygotes = 0); grpmax FAF= 0.00035972.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000106072; MAF= 0.01061%, 30/282826 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000653253; MAF= 0.06533%, 20/30616 alleles, homozygotes = 0); grpmax FAF= 0.00043223.
ClinVar
This variant has been reported in ClinVar as Likely benign (8 clinical laboratories) and as Benign (3 clinical laboratories).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Functional
OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).
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.