BRCA1 c.2967T>C, p.Phe989=
NM_007294.4:c.2967T>C
Variant of Uncertain Significance (VUS)
This synonymous BRCA1 c.2967T>C (p.F989=) variant is present at low frequency in population databases and shows no predicted splicing or functional impact. Only BP4 is met at supporting strength, with no other criteria fulfilled, resulting in a classification of Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
BP4
Genetic Information
Gene & Transcript Details
Gene
BRCA1
Transcript
NM_007294.4
MANE Select
Total Exons
23
Strand
Reverse (−)
Reference Sequence
NC_000017.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_007294.2 | Alternative | 23 exons | Reverse |
| NM_007294.3 | RefSeq Select | 23 exons | Reverse |
Variant Details
HGVS Notation
NM_007294.4:c.2967T>C
Protein Change
F989=
Location
Exon 10
(Exon 10 of 23)
5'Exon Structure (23 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_007294.4
Genome Browser
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HGVS InputNM_007294:c.2967T>C
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000399%
Extremely Rare
Highest in Population
South Asian
0.00327%
Rare
Global: 0.000399%
South Asian: 0.00327%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 250564Alt: 1Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000399%, 1/250564 alleles, homozygotes = 0) and at a higher frequency in the South Asian population (MAF= 0.00327%, 1/30606 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
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
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: -0.10
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PVS1 is: 'Null variant (nonsense, frameshift, splice site (donor/acceptor +/-1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.' The evidence for this variant shows it is a synonymous (silent) change with no predicted truncation or LOF. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: 'Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.' The evidence for this variant shows no amino acid change (F989=) and no matching known pathogenic variant. Therefore, this criterion is not applied.
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.' There is no de novo or pedigree information available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: 'Well-established in vitro or in vivo functional studies supportive of a damaging effect.' No functional assay data are available for this variant. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: 'The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls (p ≤0.05, OR ≥4).' No case-control or affected cohort data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: 'Located in a mutational hot spot or well‐established functional domain without benign variation.' This variant is a synonymous change outside of any clinically important BRCA1 functional domain. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM2 is: 'Supporting: Absent from controls in an outbred population (gnomAD v2.1 non-cancer and v3.1 non-cancer).' The evidence for this variant shows it is present at low frequency in gnomAD (MAF=0.000399%), so it is not absent. Therefore, this criterion is not applied.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: 'For patient with phenotype consistent with BRCA1‐ or BRCA2‐related Fanconi Anemia and co‐occurrence of variants in trans.' No Fanconi Anemia phenotype or trans variant data are available. Therefore, this criterion is not applied.
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.' This variant is synonymous with no length change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: 'Protein termination codon variant in an exon where a different proven pathogenic PTC variant has been seen before.' This variant is not a termination codon change. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, without confirmation of paternity and maternity.' No such data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: 'Co-segregation with disease in multiple affected family members.' No segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with low rate of benign missense variants.' This variant is synonymous, not missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: 'Supporting: In silico predictions of deleterious effect on protein or splicing (BayesDel no-AF ≥0.28 or SpliceAI ≥0.2).' The evidence shows SpliceAI score of 0.01 and CADD of -0.10, indicating no deleterious prediction. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: 'Supporting: Specific phenotype or family history for disease with high heterogeneity.' No specific familial or clinical data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic.' This variant is not found in ClinVar or other expert sources. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: 'Stand Alone: Filter allele frequency above 0.1% in gnomAD non‐cancer.' The variant frequency (0.000399%) is below 0.1%. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: 'Strong: Filter allele frequency above 0.01%.' The variant frequency (0.000399%) is below 0.01%. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: 'Strong: Observed in healthy individuals in absence of recessive phenotype.' Population data alone without phenotype confirmation do not meet BS2 criteria. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: 'Strong: Well‐established functional studies show no damaging effect.' No functional assays have been performed. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: 'Strong: Lack of segregation in affected members.' No segregation analysis is available. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP1 is: 'Strong: Silent or in‐frame variant outside functional domain with no splicing predicted.' This variant is silent but VCEP BP1 is defined for missense/in‐frame variants; synonymous classification falls under BP7 or BP4. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant in a disorder for which two variants are needed.' No such co‐occurrence data are available. Therefore, BP2 is not applied.
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.' Not applicable to a synonymous SNV. Therefore, BP3 is not applied.
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 (conservation, evolutionary, splicing impact, etc.).' The evidence for this variant shows a CADD score of -0.10 and SpliceAI maximum score of 0.01 indicating no predicted impact. Therefore, BP4 is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: 'Supporting: Co‐observation with pathogenic variant in another gene without specific phenotype.' No such co‐occurrence data are present. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign.' No external expert classifications are available. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence or create a new splice site.' While computational evidence shows no splice impact, VCEP guidelines do not define BP7 for silent variants outside functional domains without mRNA assay data. Therefore, BP7 is not applied.