BRCA1 c.-96G>C, p.?
NM_007294.4:c.-96G>C
Variant of Uncertain Significance (VUS)
The variant c.-96G>C in BRCA1 is noncoding, extremely rare, and computationally predicted to have no impact on splicing or protein. It meets PM2_Supporting, BP4_Supporting, and BP7_Supporting, but conflicting supporting pathogenic evidence (PM2) prevents resolution to Likely Benign. Therefore, the variant remains classified as a Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
BP4
BP7
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.-96G>C
Protein Change
?
Location
Exon 1
(Exon 1 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.-96G>C
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000796%
Very Rare
Highest in Population
African/African American
0.0168%
Low Frequency
Global: 0.000796%
African/African American: 0.0168%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 125634Alt: 1Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000796%, 1/125634 alleles, homozygotes = 0) and at a higher frequency in the African/African American population (MAF= 0.0168%, 1/5964 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: 0.04
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines for BRCA1, PVS1 applies only to null variants (nonsense, frameshift, canonical ±1,2 splice sites, initiation codon, single/multiexon deletions) in a gene where LOF is a known mechanism of disease. The evidence for this variant shows: c.-96G>C is located in the 5' UTR upstream of the start codon and is not predicted to create a null effect. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS1 applies when a variant results in the same amino acid change as a known pathogenic variant. The evidence for this variant shows: it is noncoding (no amino acid change). Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 applies when a variant is confirmed de novo with maternity and paternity established. The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS3 applies when well-established in vitro or in vivo functional studies show a damaging effect. The evidence for this variant shows: no functional studies have been performed for c.-96G>C. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS4 applies when the variant is significantly enriched in affected individuals compared to controls. The evidence for this variant shows: no case-control or patient data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines for BRCA1, PM1 applies to variants in mutational hotspots or functional domains. The evidence for this variant shows: c.-96G>C is located in the 5' UTR outside of known protein domains. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines for BRCA1, PM2 Supporting is defined as: "Absent from controls in an outbred population, from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer)." The evidence for this variant shows: the variant is extremely rare (MAF = 0.00000796 in gnomAD). Therefore, this criterion is applied at Supporting strength because the variant is absent or extremely rare in population databases.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines for BRCA1, PM3 applies to biallelic occurrences in Fanconi anemia patients. The evidence for this variant shows: no Fanconi anemia case or co-occurring variant data. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 applies to protein length changes (in-frame indels). The evidence for this variant shows: no change to protein length (noncoding variant). Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines for BRCA1, PM5 applies to premature termination codons in exons where other PTCs have been seen. The evidence for this variant shows: c.-96G>C does not introduce a PTC. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 applies to assumed de novo cases without confirmation. 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 for BRCA1, PP1 applies to co-segregation with disease in multiple affected family members. The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies to missense variants in a gene with low rate of benign missense variation where missense is a common mechanism. The evidence for this variant shows: it is noncoding. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines for BRCA1, PP3 Supporting applies for predicted splicing impact (SpliceAI ≥0.2) or damaging protein effect (BayesDel no-AF ≥0.28). The evidence for this variant shows: SpliceAI maximum score 0.03 (<0.2) and CADD score 0.04, indicating no predicted impact. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines for BRCA1, PP4 applies when combined clinical data (multifactorial likelihood) indicate pathogenicity. The evidence for this variant shows: no clinical phenotype data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 applies when a reputable source reports the variant as pathogenic without available evidence. The evidence for this variant shows: not found in ClinVar or other reputable databases. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines for BRCA1, BA1 applies when the filter allele frequency (FAF) exceeds 0.1%. The evidence for this variant shows: MAF = 0.00000796 (0.000796%), which is below the 0.1% threshold. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines for BRCA1, BS1 Strong applies when FAF >0.01%. The evidence for this variant shows: MAF = 0.00000796 (0.000796%), which is below 0.01%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines for BRCA1, BS2 applies when the variant is observed in healthy adults without a disease phenotype. The evidence for this variant shows: no healthy individual data. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines for BRCA1, BS3 applies when well-established functional studies show no damaging effect. The evidence for this variant shows: no functional studies are available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines for BRCA1, BS4 applies to lack of segregation in affected family members. 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 for BRCA1, BP1_Strong applies to silent or in-frame variants outside functional domains with no predicted splice effect. The evidence for this variant shows: variant is noncoding but outside splice sites; however, BP7 is more specific. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies when a variant is observed in trans with a pathogenic variant in a 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, BP3 applies to in-frame deletions/insertions in repetitive regions without known function. The evidence for this variant shows: not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines for BRCA1, BP4 Supporting is defined as: "Intronic variants outside of the native donor and acceptor splice sites (i.e., not +/-1,2 positions) AND no predicted impact via splicing (SpliceAI ≤0.1)." The evidence for this variant shows: c.-96G>C is outside splice sites and SpliceAI max score 0.03. Therefore, this criterion is applied at Supporting strength because multiple in silico tools predict no impact.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines for BRCA1, BP5 applies to co-observation with pathogenic variants in other genes indicating no specific phenotype. The evidence for this variant shows: no such co-observation. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 applies when a reputable source reports the variant as benign without available evidence. The evidence for this variant shows: no such report. Therefore, this criterion is not applied.
BP7
BP7 (Supporting)
According to VCEP guidelines for BRCA1, BP7 Supporting is defined as: "Intronic variants located outside conserved donor or acceptor motif positions (at or beyond positions +7/-21) IF BP4 met." The evidence for this variant shows: c.-96G>C is more than 21 bp from splice sites, and BP4 was met. Therefore, this criterion is applied at Supporting strength.