BRIP1 c.1800T>G, p.Phe600Leu
NM_032043.3:c.1800T>G
COSMIC ID: COSM7357748
Variant of Uncertain Significance (VUS)
This legacy system is being phased out as Project HERA V3 is rolled out.
ACMG/AMP Criteria Applied
PM2
BP1
BP4
Genetic Information
Gene & Transcript Details
Gene
BRIP1
Transcript
NM_032043.3
MANE Select
Total Exons
20
Strand
Reverse (−)
Reference Sequence
NC_000017.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_032043.2 | RefSeq Select | 20 exons | Reverse |
| NM_032043.1 | Alternative | 20 exons | Reverse |
Variant Details
HGVS Notation
NM_032043.3:c.1800T>G
Protein Change
F600L
Location
Exon 13
(Exon 13 of 20)
5'Exon Structure (20 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 600 in gene BRIP1
Alternate Identifiers
COSM7357748
Variant interpretation based on transcript NM_032043.3
Genome Browser
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HGVS InputNM_032043:c.1800T>G
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000398%
Extremely Rare
Highest in Population
African/African American
0.00616%
Rare
Global: 0.000398%
African/African American: 0.00616%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 251362Alt: 1Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000398%, 1/251362 alleles, homozygotes = 0) and at a higher frequency in the African/African American population (MAF= 0.00616%, 1/16238 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Uncertain Significance (VUS)
Based on 4 submitter reviews in ClinVar
Submitter Breakdown
4 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 600 in gene BRIP1
Functional Summary
The BRIP1 F600L variant has not been functionally characterized, and its effect on Brip1 protein function is unknown.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damaging
Benign:
CADD: 4.36metasvm: Tmetalr: Tprimateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multi-exon deletion in a LoF gene) in a gene where LOF is a known mechanism of disease". The evidence for this variant shows: it is a missense change (F600L) and does not introduce a null effect. Therefore, this criterion is not applied because the variant is not a null variant.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a known pathogenic variant but different nucleotide change". The evidence for this variant shows: there is no previously established pathogenic variant resulting in F600L. Therefore, this criterion is not applied because there is no matching pathogenic amino acid change.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". The evidence for this variant shows: no de novo testing or family history data are available. Therefore, this criterion is not applied due to lack of de novo confirmation.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: "Well-established functional studies supportive of a damaging effect on the gene or gene product". The evidence for this variant shows: there are no functional studies characterizing the effect of F600L on BRIP1 function. Therefore, this criterion is not applied because functional impact has not been demonstrated.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence in affected individuals significantly increased compared with controls". The evidence for this variant shows: no case–control or cohort data comparing affected versus control frequencies. Therefore, this criterion is not applied because statistical association data are unavailable.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot or well-established functional domain without benign variation". The evidence for this variant shows: there is no evidence that F600 resides within a known hotspot or critical domain lacking benign variation. Therefore, this criterion is not applied due to lack of domain or hotspot data.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive)". The evidence for this variant shows: extremely low population frequency (MAF=0.000398% in gnomAD). Therefore, this criterion is applied at Moderate strength because the variant is absent or at extremely low frequency in controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant (for recessive disorders)". The evidence for this variant shows: no data on phase or compound heterozygosity. Therefore, this criterion is not applied because phasing information is unavailable.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants". The evidence for this variant shows: it is a single amino acid substitution without change in protein length. Therefore, this criterion is not applied because there is no in-frame indel or stop-loss.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen". The evidence for this variant shows: no pathogenic missense changes reported at residue F600. Therefore, this criterion is not applied because no other pathogenic variant at this residue exists.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: no de novo or parental testing data. Therefore, this criterion is not applied due to lack of assumed de novo evidence.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members". The evidence for this variant shows: no family segregation data are available. Therefore, this criterion is not applied because segregation information is missing.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease". The evidence for this variant shows: BRIP1 disease mechanism is predominantly loss-of-function rather than missense. Therefore, this criterion is not applied because missense is not established as a common pathogenic mechanism.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene or gene product". The evidence for this variant shows: computational tools are predominantly benign and SpliceAI predicts no splicing impact. Therefore, this criterion is not applied because computational evidence does not support pathogenicity.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient’s phenotype or family history highly specific for a disease with a single genetic etiology". The evidence for this variant shows: no phenotype or family history data provided. Therefore, this criterion is not applied because phenotype specificity is not documented.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic, but without accessible evidence". The evidence for this variant shows: ClinVar reports uncertain significance, not pathogenic. Therefore, this criterion is not applied because no reputable source classifies this variant as pathogenic.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder". The evidence for this variant shows: MAF=0.000398%, which is well below the 5% threshold. Therefore, this criterion is not applied because allele frequency is not high enough.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for disorder". The evidence for this variant shows: frequency remains below disease-specific thresholds. Therefore, this criterion is not applied because frequency does not exceed expected for BRIP1-related disease.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult individual for a dominant disorder with full penetrance". The evidence for this variant shows: only allele counts in population databases without phenotypic information. Therefore, this criterion is not applied because healthy adult status is not documented.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect on protein function or splicing". The evidence for this variant shows: no functional studies exist. Therefore, this criterion is not applied because functional evidence is lacking.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected family members". The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied because segregation analysis is not available.
BP1
BP1 (Supporting)
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only loss-of-function causes disease". The evidence for this variant shows: BRIP1-associated disease mechanism is loss-of-function and F600L is missense. Therefore, this criterion is applied at Supporting strength because missense variants are not a known disease mechanism in this gene.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant". The evidence for this variant shows: no data on cis/trans occurrence with pathogenic variants. Therefore, this criterion is not applied because phase information is unavailable.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without known function". The evidence for this variant shows: this is a single nucleotide substitution, not an indel. Therefore, this criterion is not applied because it is not an in-frame indel.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product". The evidence for this variant shows: in silico tools (CADD, MetaSVM, MetaLR, PrimateAI) predict benign effect and SpliceAI predicts no splicing impact. Therefore, this criterion is applied at Supporting strength because computational evidence supports a benign effect.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease". The evidence for this variant shows: no case reports with another molecular cause. Therefore, this criterion is not applied because alternate molecular etiology is not documented.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign, but without accessible evidence". The evidence for this variant shows: ClinVar reports uncertain significance, not benign. Therefore, this criterion is not applied because no reputable benign assertion exists.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing". The evidence for this variant shows: it is a missense, not synonymous. Therefore, this criterion is not applied because the variant does not meet the synonymous definition.