About BRIP1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
BRIP1 c.611C>G, p.(Ser204Cys)
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 absent from all large population databases including gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, with an allele frequency well below the 0.1% threshold for PM2.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no impact on gene product: REVEL score 0.24 (below pathogenic threshold), BayesDel score -0.212 (benign-polar), and SpliceAI max delta 0.00 (no predicted splicing alteration).
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 + 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.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
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
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 13 not met · 8 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_032043.3:c.611C>G (p.Ser204Cys) is a missense variant in BRIP1 that is absent from all large population databases including gnomAD v2.1, v4.1, and gnomAD-Canada.
Multiple in silico predictors (REVEL 0.24, BayesDel -0.212, SpliceAI max delta 0.00) indicate this variant is tolerated and does not affect splicing.
No variant-specific functional studies, case-control data, co-segregation data, or de novo observations were identified for this variant in the peer-reviewed literature.
Applying generic ACMG/AMP 2015 classification rules (PMID:25741868): one moderate pathogenic criterion (PM2) and one supporting benign criterion (BP4) are met, resulting in insufficient evidence for classification; the variant is a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 ModerateThis variant is absent from all large population databases including gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, with an allele frequency well below the 0.1% threshold for PM2. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent (AF=null)
- gnomAD v4.1: absent (AF=null)
- gnomAD-Canada v1.0: absent (AC=0
- AN=0)
Sources
BP4 SupportingMultiple lines of computational evidence suggest no impact on gene product: REVEL score 0.24 (below pathogenic threshold), BayesDel score -0.212 (benign-polar), and SpliceAI max delta 0.00 (no predicted splicing alteration). Details ▾Hide ▴
Evidence considered
- REVEL: 0.24
- BayesDel: -0.212
- SpliceAI max delta: 0.00 — all three in silico tools predict a benign effect.
Sources
Not met · 13 · evaluated, threshold not reached
PS3 No well-established in vitro or in vivo functional studies demonstrating a damaging effect of p.Ser204Cys on BRIP1 protein function have been identified in the peer-reviewed literature. Details ▾Hide ▴
Evidence considered
- A 2024 bioRxiv preprint (Putnam et al.) from exploratory search suggests near-wildtype function for S204C in a multiplexed assay
- but this is not peer-reviewed and supports a benign rather than damaging interpretation.
Still missing
- No peer-reviewed functional data for p.Ser204Cys
- preprint data not yet validated.
PS4 No case-control studies demonstrate a statistically significant enrichment of this variant in affected individuals compared to population controls. Details ▾Hide ▴
Evidence considered
- Variant is absent from gnomAD v2.1
- v4.1
- and gnomAD-Canada
- but absence from controls alone does not constitute case-control evidence for PS4.
Still missing
- No case-control or odds-ratio data available.
PM1 Residue 204 lies within the DEAD-like helicase domain (residues ~1-440) but is not located within a defined mutational hotspot or a critical functional domain with established clustering of pathogenic missense variants. Details ▾Hide ▴
Evidence considered
- No statistically significant hotspot at codon 204
- no enrichment of pathogenic missense variants at this residue in ClinVar.
Still missing
- Domain-level functional mapping for BRIP1 missense variants is incomplete.
PM6 No reports of a de novo occurrence of this variant without confirmation of parental identity were identified. Details ▾Hide ▴
Still missing
- No de novo observations reported.
PP1 No co-segregation data with disease in families harboring this variant have been published; no LOD scores or pedigree analyses are available. Details ▾Hide ▴
Still missing
- No family segregation studies identified.
PP2 Insufficient evidence that BRIP1 has a low rate of benign missense variation and that missense variants are a common mechanism of disease; many BRIP1 missense variants remain classified as VUS. Details ▾Hide ▴
Still missing
- No gene-level constraint metrics (e.g.
- missense Z-score
- o/e) confirming low benign missense rate for BRIP1.
PP3 Multiple in silico predictors do not support a deleterious effect: REVEL score 0.24 (below 0.5 damaging threshold), BayesDel score -0.212 (benign-polar), and SpliceAI max delta 0.00 (no splicing impact predicted). Details ▾Hide ▴
Evidence considered
- REVEL: 0.24
- BayesDel: -0.212
- SpliceAI max delta: 0.00
Sources
PP5 No reputable source (e.g., clinical diagnostic laboratory, expert panel) recently reports this variant as pathogenic without supporting evidence available for independent evaluation. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar
- no reputable source has classified this variant.
BA1 This variant is absent from all large population databases (gnomAD v2.1, v4.1, gnomAD-Canada); allele frequency of 0 does not exceed the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
- Allele frequency: 0 in all population databases.
Sources
BS1 This variant is absent from all population databases; allele frequency of 0 does not exceed the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
- Allele frequency: 0 in all population databases.
Sources
BS2 No evidence that this variant has been observed in homozygous state, in trans with a pathogenic variant, or in healthy adult individuals with full penetrance expected at an early age. Details ▾Hide ▴
Still missing
- No observation data in healthy individuals.
BP1 Although BRIP1 loss-of-function is an established disease mechanism, pathogenic missense variants have been reported in BRIP1; insufficient evidence exists to conclude that primarily truncating variants are known to cause BRIP1-related disease to the exclusion of missense variants. Details ▾Hide ▴
Still missing
- No systematic analysis comparing pathogenic missense vs. truncating variant burden in BRIP1.
BP6 No reputable source (e.g., clinical diagnostic laboratory, expert panel) recently reports this variant as benign without supporting evidence available for independent evaluation. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar
- no reputable source has classified this variant.
Not assessed · 8 · no assessment recorded
PS1 No alternate nucleotide change at codon 204 leading to the same p.Ser204Cys missense change has been identified in ClinVar or the literature as pathogenic; PS1 cannot be assessed. Details ▾Hide ▴
Still missing
- No same-amino-acid comparator variant identified at codon 204.
PS2 No reports of de novo occurrence of this variant (with confirmed maternity and paternity) were identified in the literature or databases. Details ▾Hide ▴
Still missing
- No de novo observation data available.
PM5 No pathogenic missense variants at codon 204 involving a different amino acid change were identified in ClinVar; PM5 cannot be assessed without a same-residue comparator. Details ▾Hide ▴
Evidence considered
- PM5 candidate harvesting returned 0 same-residue candidates.
Still missing
- No same-residue pathogenic comparator variants available.
PP4 No patient phenotype or family history information is available for this case to assess specificity of clinical presentation. Details ▾Hide ▴
Still missing
- No clinical phenotype or family history data provided.
BS3 A 2024 bioRxiv preprint (Putnam et al.) from exploratory search suggests p.Ser204Cys has near-wildtype function in a multiplexed assay of variant effect; however, these data are not peer-reviewed and a single preprint does not constitute well-established functional evidence sufficient to meet BS3. Details ▾Hide ▴
Evidence considered
- Exploratory search identified a bioRxiv preprint suggesting functional tolerance of S204C
- but peer-reviewed publication status is unconfirmed.
Still missing
- Preprint functional data requires peer review and replication
- MaveDB entry not confirmed.
BS4 No segregation data demonstrating lack of co-segregation with disease in affected families are available. Details ▾Hide ▴
Still missing
- No family segregation data available.
BP2 This variant has not been observed in trans with a known pathogenic BRIP1 variant in an individual with a fully penetrant dominant disorder, nor in cis with a pathogenic BRIP1 variant. Details ▾Hide ▴
Still missing
- No cis or trans observations with another BRIP1 pathogenic variant.
BP5 No clinical case information is available demonstrating an alternate molecular basis for disease in a proband harboring this variant. Details ▾Hide ▴
Still missing
- No clinical phenotype or alternate molecular diagnosis data provided.
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_032043.3:c.611C>G is a missense variant (p.Ser204Cys) and does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants; PVS1 is not applicable. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- apply_generic_pvs1_framework=false per PVS1 variant assessment.
Sources
PM3 N/ASkipped per instructions: PM3 applies to recessive disorders with in trans observation; BRIP1 germline context is dominant cancer predisposition and no in trans data exist. Details ▾Hide ▴
No further detail was recorded.
PM4 N/ASkipped per instructions: PM4 applies to in-frame deletions/insertions or stop-loss variants; this is a missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ASkipped per instructions: BP3 applies to in-frame deletions/insertions in repeating regions; this is a missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous (silent) variants; NM_032043.3:c.611C>G is a missense variant (p.Ser204Cys). Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 is not a criterion in the standard ACMG/AMP 2015 framework (PMID:25741868); no BRIP1-specific VCEP defines an extended PS5 rule. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- BRIP1
- Transcript
- NM_032043.3
- Coding (HGVS c.)
- NM_032043.3:c.611C>G
- Protein (HGVS p.)
- NP_114432.2:p.(Ser204Cys)
- GRCh38
- chr17:61847117 G>C
- GRCh37
- chr17:59924478 G>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…
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
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
Other predictors
- REVEL
- 0.240
- BayesDel
- -0.212
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no impact on gene product: REVEL score 0.24 (below pathogenic threshold), BayesDel score -0.212 (benign-polar), and SpliceAI max delta 0.00 (no predicted splicing alteration). Details ▾Hide ▴
Evidence considered
- REVEL: 0.24
- BayesDel: -0.212
- SpliceAI max delta: 0.00 — all three in silico tools predict a benign effect.
Sources
PP3 Multiple in silico predictors do not support a deleterious effect: REVEL score 0.24 (below 0.5 damaging threshold), BayesDel score -0.212 (benign-polar), and SpliceAI max delta 0.00 (no splicing impact predicted). Details ▾Hide ▴
Evidence considered
- REVEL: 0.24
- BayesDel: -0.212
- SpliceAI max delta: 0.00
Sources
BP7 N/ABP7 applies to synonymous (silent) variants; NM_032043.3:c.611C>G is a missense variant (p.Ser204Cys). 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 = 0.24. BayesDel score = -0.212169.
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 0.000
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/?term=NM_032043.3%3Ac.611C%3EG
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-59924478-G-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-61847117-G-C?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-61847117-G-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_032043.3%3Ac.611C…
- OncoKB ↗www.oncokb.org/gene/BRIP1/S204C
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=BRIP1+c.611C%3EG
- 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
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 = 0.00). REVEL score = 0.24. BayesDel score = -0.212169.
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.