BRCA1 c.594-15G>C, p.?
NM_007294.4:c.594-15G>C
Variant of Uncertain Significance (VUS)
The variant c.594-15G>C in BRCA1 remains a VUS due to one supporting pathogenic code (PM2) balanced by two supporting benign codes (BP4, BS1), with insufficient additional evidence to resolve conflicting supporting criteria.
ACMG/AMP Criteria Applied
PM2
BS1
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.594-15G>C
Protein Change
?
Location
Exon 8
(Exon 8 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.594-15G>C
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00202%
Rare
Highest in Population
European (non-Finnish)
0.00447%
Rare
Global: 0.00202%
European (non-Finnish): 0.00447%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 248052Alt: 5Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00202%, 5/248052 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.00447%, 5/111952 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
1 publications
Uncertain Significance (VUS)
Based on 6 submitter reviews in ClinVar
Submitter Breakdown
1 VUS
5 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
Variant summary: BRCA1 c.594-15G>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Computational tools predict no significant impact on normal splicing, and these predictions were confirmed by one splicing study (Houdayer_2012). The variant allele was found at a frequency of 2e-05 in 248052 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.594-15G>C has been reported in the literature in individuals affected with Breast Cancer (Wong-Brown_2015). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with at least one other pathogenic variant has been reported in the NHGRI database (BRCA2 c.5576_5579delTTAA, p.Ile1859fsX3), providing supporting evidence for a benign role. The following publications have been ascertained in the context of this evaluation (PMID: 22505045, 25682074). Four ClinVar submitters have assessed the variant since 2014, and all four classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratories) and as Likely benign (5 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: 0.88
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 (LOF) is a known mechanism of disease.' The evidence for this variant shows it is an intronic change at position -15, outside the canonical splice sites (+/−1,2) and not a truncating or null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: 'Strong: Apply PS1 for exonic and intronic variants with same predicted impact on splicing, as a previously classified pathogenic variant.' The evidence for this variant shows no previously established pathogenic variant with identical splicing impact. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 is: 'Strong: De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.' There is no de novo evidence available for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: 'Strong: Well-established in vitro or in vivo functional studies supportive of a damaging effect.' No functional studies have been performed for this variant. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: 'Strong: The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls (case-control studies; p-value ≤0.05 and OR ≥4).' There are no case-control or patient prevalence data for this variant. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM1 is: 'Moderate: Located in a mutational hot spot and/or critical and well-established functional domain without benign variation.' This variant is intronic and outside any known functional domain. 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) and gnomAD v3.1 (non-cancer).' The evidence for this variant shows it is extremely rare or absent (MAF = 0.00202%). Therefore, PM2 is applied at supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 (Supporting) is: 'Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA) and co-occurrent variants in the same gene.' There is no FA patient or co-occurrence data. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 is: 'Moderate: Protein length changes as a result of in-frame deletions/insertions or stop-loss variants.' This variant is intronic and does not alter protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM5 is: 'Moderate: Novel missense change at an amino acid residue where a different missense change has been determined to be pathogenic.' This variant does not change an amino acid residue. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 is: 'Supporting: Assumed de novo, but without confirmation.' There is no evidence for de novo occurrence. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 (Supporting) is: 'Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.' No family segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 is: 'Supporting: Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.' This variant is intronic. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3 (Supporting) is: 'Apply for predicted splicing (SpliceAI ≥0.2) for intronic variants outside of donor and acceptor 1,2 positions.' SpliceAI predicts no significant impact (max score 0.08). Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, PP4 (Supporting) is: 'Breast cancer is very common and has a high degree of genetic heterogeneity; use only to capture combined LR towards pathogenicity based on multifactorial likelihood clinical data.' No such clinical data are available. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 is: 'Supporting: Reputable source reports variant as pathogenic.' ClinVar reports conflicting interpretations including likely benign. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 is: 'Stand Alone: Filter allele frequency (FAF) is above 0.1% in gnomAD.' The variant's MAF (0.00202%) is well below 0.1%. Therefore, this criterion is not applied.
BS1
BS1 (Supporting) Strength Modified
According to VCEP guidelines, BS1 (Supporting) is: 'Filter allele frequency (FAF) is above 0.002% and ≤0.01% in gnomAD.' The variant's MAF (0.00202%) is above 0.002% and within ≤0.01%. Therefore, BS1 is applied at supporting strength.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 (Supporting) is: 'Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype.' There is no phenotypic data to confirm absence of FA. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 (Strong) is: 'Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.' No such functional studies exist for this variant. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 (Strong) is: 'Lack of segregation in affected members of a family, as measured by quantitative co-segregation analysis.' No segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines, BP1 (Supporting) is: 'Silent substitution, missense or in-frame insertion/deletion variants outside a clinically important functional domain and no splicing predicted.' This variant is intronic. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 is: 'Supporting: Observed in trans with a pathogenic variant in a recessive gene.' No such observations are reported. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 is: 'Supporting: In-frame deletions/insertions in a repetitive region without a known function.' This variant is not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, BP4 (Supporting) is: 'Intronic variants outside of native donor and acceptor splice sites (not ±1,2 positions) and no predicted impact via splicing (SpliceAI ≤0.1).' SpliceAI score is 0.08. Therefore, BP4 is applied at supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, BP5 (Supporting) is: 'Use only to capture combined LR against pathogenicity based on multifactorial likelihood clinical data for cases with pathogenic variants in two different genes.' There is no co-occurrence data. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 is: 'Supporting: Reputable source reports variant as benign.' Existing ClinVar entries are conflicting and not definitive. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 (Supporting) is: 'Intronic variants located outside conserved donor or acceptor motif positions (at or beyond positions +7/−21) if BP4 met.' This variant is at position −15, which is not beyond −21. Therefore, this criterion is not applied.