BRCA1 c.4358-22T>G, p.?
NM_007294.4:c.4358-22T>G
Variant of Uncertain Significance (VUS)
The variant c.4358-22T>G in BRCA1 remains a Variant of Uncertain Significance as only two supporting criteria (PM2, PP3) are met, which is insufficient for a benign or pathogenic 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.4358-22T>G
Protein Change
?
Location
Exon 12
(Exon 12 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.4358-22T>G
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
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: 0.98
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), initiation codon, single or multi-exon deletion) in a gene where loss of function is a known mechanism of disease.' The evidence for this variant shows: it is an intronic change at c.4358-22T>G, located outside the ±1,2 canonical splice sites. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: 'Apply PS1 for predicted missense substitutions or exonic/intronic variants with the same predicted impact on splicing as a previously classified pathogenic variant.' The evidence for this variant shows: there is no known pathogenic variant with the same predicted transcript or protein impact. 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 information on de novo status is 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 on the gene or gene product.' The evidence for this variant shows: no functional assays have been performed for c.4358-22T>G. 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 and OR ≥ 4).' The evidence for this variant shows: no case-control data or enrichment in affected individuals. 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 and/or critical and well-established functional domain without benign variation.' The evidence for this variant shows: it is an intronic change 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 (non-cancer, exome only) and gnomAD v3.1 (non-cancer).' The evidence for this variant shows: MAF = 0% and absence from gnomAD databases. Therefore, this criterion is applied at Supporting strength because the variant is absent in population controls.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: 'Apply for a patient with phenotype consistent with BRCA1-related Fanconi Anemia and co-occurring variants in the same gene.' The evidence for this variant shows: no Fanconi Anemia phenotype data or co-occurrence information. 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 as a result of in-frame deletions/insertions in a non-repeat region or stop-loss variants.' The evidence for this variant shows: it is intronic and does not alter protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: 'Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen.' The evidence for this variant shows: it is an intronic change and not a PTC. 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, but without confirmation of paternity and maternity.' The evidence for this variant shows: no de novo evidence. 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 in a gene definitively known to cause the disease.' 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 a low rate of benign missense variation and where missense variants are a common mechanism of disease.' The evidence for this variant shows: it is intronic, not missense. 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 silent, missense/in-frame and intronic variants outside of donor and acceptor 1,2 sites.' The evidence for this variant shows: a SpliceAI acceptor loss score of 0.31, exceeding the 0.2 threshold. Therefore, this criterion is applied at Supporting strength because the variant is predicted to impact splicing.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: 'Breast cancer is very common and highly heterogeneous; use only to capture combined LR towards pathogenicity based on multifactorial likelihood clinical data.' The evidence for this variant shows: no multifactorial clinical 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 without available evidence.' The evidence for this variant shows: not reported in ClinVar or other databases. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: 'Stand Alone FAF >0.001 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: 'Filter allele frequency >0.0001 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 features of recessive disease (Fanconi Anemia) with ≥4 points.' The evidence for this variant shows: no data on absence in healthy adults or recessive phenotype. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: 'Well-established functional studies show no damaging effect on protein function.' The evidence for this variant shows: no functional studies available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: 'Lack of segregation in affected family members (LR ≤0.05).' The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP1 is: 'Silent substitution, missense or in-frame variant outside clinically important functional domains with no splicing predicted (SpliceAI ≤0.1).' The evidence for this variant shows: SpliceAI = 0.31, exceeding 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 fully penetrant dominant 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 deletions/insertions in a repetitive region without a known function.' The evidence for this variant shows: it is an intronic single-nucleotide change. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: 'Missense/in-frame or intronic variants outside donor/acceptor sites with no predicted impact via splicing (SpliceAI ≤0.1).' The evidence for this variant shows: SpliceAI = 0.31, above the threshold. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: 'Co-observation with pathogenic variant in another breast–ovarian cancer gene without specific phenotype.' The evidence for this variant shows: no co-observation 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 without evidence.' The evidence for this variant shows: no such reports. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: 'Intronic variants outside conserved donor/acceptor motifs at or beyond positions +7/−21 if BP4 met.' The evidence for this variant shows: although at −22, BP4 is not met. Therefore, this criterion is not applied.