BRCA1 c.80+5G>A, p.?
NM_007294.4:c.80+5G>A
Variant of Uncertain Significance (VUS)
BRCA1 c.80+5G>A is classified as a Variant of Uncertain Significance (VUS) based on the application of PM2_Supporting and PP3_Supporting only, with insufficient evidence to meet criteria for pathogenic or benign classification.
ACMG/AMP Criteria Applied
PM2
PP3
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.80+5G>A
Protein Change
?
Location
Exon 2
(Exon 2 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.80+5G>A
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
2 publications
Likely Pathogenic
Based on 5 submitter reviews in ClinVar
Submitter Breakdown
2 Path
1 LP
2 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (2)
The c.80+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 1 in the BRCA1 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site. In vitro cDNA analysis supports this variant as causing out-of-frame skipping of coding exon 1 and translation initiation codon loss (Ambry internal data; Baert A et al. Hum. Mutat., 2018 04;39:515-526). Similar alterations at this splice donor site through +5 have been shown to cause skipping of coding exon 1 (also known as Exon 2) with resulting loss of the start codon (Ambry internal data; Steffensen AY et al. Eur J Hum Genet. 2014 Dec;22(12):1362-8). Based on the majority of available evidence to date, this alteration is interpreted as a disease-causing mutation.
This sequence change falls in intron 2 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with breast and ovarian cancer (PMID: 29470806, 32211327). ClinVar contains an entry for this variant (Variation ID: 125520). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories) and as Pathogenic (2 clinical laboratories) and as Likely pathogenic (1 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
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 3.30
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: 'Very Strong Null variant (nonsense, frameshift, splice site (donor/acceptor +/−1,2) in a gene where loss of function is a known mechanism of disease.' The evidence for this variant shows it is at the +5 position, outside the canonical ±1,2 splice sites. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG 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 previously established pathogenic variant with the same predicted splicing impact or amino acid change. 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.' The evidence for this variant shows no parental testing data available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: 'Well-established in vitro or in vivo functional studies supportive of a damaging effect.' The evidence for this variant shows no functional studies have been performed. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: 'The prevalence of the variant in affected individuals is significantly increased compared to controls.' The evidence for this variant shows no case-control or aggregate clinical data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: 'Located in a mutational hot spot or well-studied functional domain without benign variation.' The evidence for this variant shows it is an intronic variant outside known functional domains. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: 'Supporting Absent from controls in an outbred population, from gnomAD v2.1 and v3.1.' The evidence for this variant shows it is absent from gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: 'Supporting Apply for patient with phenotype consistent with BRCA1-related Fanconi Anemia and co-occurring variants.' The evidence for this variant shows no Fanconi Anemia phenotype data. 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 indels or stop-loss.' The evidence for this variant shows no protein length change as it is an intronic variant. Therefore, this criterion is not applied.
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 before.' The evidence for this variant shows no relevant missense or PTC context. 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/maternity.' The evidence for this variant shows no family data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: 'Supporting Co-segregation with disease in multiple affected family members.' The evidence for this variant shows no segregation data 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 variation and where missense variants are common mechanism.' The evidence for this variant shows it is intronic. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3 is: 'Supporting Apply PP3 for predicted splicing (SpliceAI ≥0.2) for intronic variants outside of donor and acceptor 1,2 sites.' The evidence for this variant shows SpliceAI predicts donor loss (0.90) and acceptor loss (0.82). Therefore, this criterion is applied at Supporting strength.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: 'Supporting Breast cancer phenotype combined clinical LR ≥2.08:1.' The evidence for this variant shows no clinical phenotype or likelihood ratio data. 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 but evidence not available for independent evaluation.' The evidence for this variant shows conflicting ClinVar interpretations (VUS, Pathogenic, Likely Pathogenic). Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP1 is: 'Strong Apply BP1 for silent substitution, missense or in-frame variant outside functional domains AND no splicing predicted (SpliceAI ≤0.1).' The evidence for this variant shows predicted splicing impact (SpliceAI >0.1). Therefore, this criterion 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 for a recessive disorder.' The evidence for this variant shows no co-occurrence data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame indel in a repetitive region without a known function.' The evidence for this variant shows it is an intronic SNV. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: 'Supporting Intronic variants outside donor/acceptor sites with no predicted splicing impact (SpliceAI ≤0.1).' The evidence for this variant shows SpliceAI scores >0.1. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: 'Supporting Combined evidence against pathogenicity based on multifactorial clinical data.' The evidence for this variant shows no multifactorial likelihood data. Therefore, this criterion 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 but no evidence available.' The evidence for this variant shows no such report. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: 'Supporting Intronic and silent variants with no predicted splicing impact (SpliceAI ≤0.1).' The evidence for this variant shows SpliceAI >0.1. 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 (FAF) >0.1% in gnomAD non-cancer populations.' The evidence for this variant shows MAF=0. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: 'Strong Filter allele frequency (FAF) >0.01% in gnomAD non-cancer populations.' The evidence for this variant shows MAF=0. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: 'Applied in absence of Fanconi Anemia phenotype features.' The evidence for this variant shows no such clinical data. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: 'Well-established in vitro or in vivo functional studies show no damaging effect.' The evidence for this variant shows no functional studies. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: 'Strong Lack of segregation in affected family members.' The evidence for this variant shows no segregation analysis. Therefore, this criterion is not applied.