BRCA1 c.3916_3917del, p.Leu1306AspfsTer23
NM_007294.4:c.3916_3917del
Pathogenic
This frameshift variant results in a premature stop codon and is absent from population databases. Functional studies and VCEP guidelines support a loss‐of‐function mechanism. Combined with recurrent pathogenic PTC evidence and reputable source classifications, the variant meets criteria for Pathogenic.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
PM5
PP5
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.3916_3917del
Protein Change
L1306Dfs*23
Location
Exon 10
(Exon 10 of 23)
5'Exon Structure (23 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 1306: L1306F
Variant interpretation based on transcript NM_007294.4
Genome Browser
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HGVS InputNM_007294:c.3916_3917del
Active Tracks
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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
4 publications
Likely Pathogenic
Based on 11 submitter reviews in ClinVar
Submitter Breakdown
10 Path
1 LP
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (4)
The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data.
The c.3916_3917delTT pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 3916 to 3917, causing a translational frameshift with a predicted alternate stop codon (p.L1306Dfs*23). This mutation has been reported in multiple patients with hereditary breast and ovarian cancer (HBOC) (De Benedetti VM et al. Oncogene, 1996 Sep;13:1353-7; Zhang J et al. Breast Cancer Res Treat, 2012 Apr;132:421-8; Cao W et al. Anat Rec (Hoboken), 2013 Feb;296:273-8; Couch FJ et al. J Clin Oncol, 2015 Feb;33:304-11; Kwong A et al. J Med Genet, 2016 Jan;53:15-23; Kim YC et al. Oncotarget, 2016 Feb;7:9600-12; Azzollini J et al. Eur J Intern Med, 2016 Jul;32:65-71; Fernandes GC et al. Oncotarget, 2016 Dec;7:80465-80481; Shi T et al. Int J Cancer, 2017 05;140:2051-2059; Zhao Q et al. J Gynecol Oncol, 2017 Jul;28:e39; Sun J et al. Clin Cancer Res, 2017 Oct;23:6113-6119; Palmero EI et al. Sci Rep, 2018 06;8:9188; Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660; Wang X et al. Mol Genet Genomic Med, 2019 06;7:e677; Concolino P et al. Int J Mol Sci, 2019 Jul;20; Zeng C et al. Breast Cancer Res Treat, 2020 Jun;181:465-473; Santonocito C et al. Cancers (Basel), 2020 May;12). This mutation has also been reported in patients with pancreatic cancer (Toss A et al. Cancers (Basel), 2019 Feb;11). This mutation has been reported to co-occur with mutations in BRCA2 (Zuradelli M et al. Breast Cancer Res. Treat. 2010 Nov;124:251-8; Rebbeck TR et al. Breast Cancer Res. 2016 Nov;18:112). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
This sequence change creates a premature translational stop signal (p.Leu1306Aspfs*23) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with a BRCA1-related disease (PMID: 8808710, 20373018, 25452441, 26187060). This variant is also known as 4035delTT (L1306fs). ClinVar contains an entry for this variant (Variation ID: 55049). For these reasons, this variant has been classified as Pathogenic.
This variant deletes 2 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 4035delTT based on the BIC nomenclature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 11044645, 15340362, 20373018, 21614564, 25452441). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (10 clinical laboratories) and as Likely pathogenic (1 clinical laboratories) and as Pathogenic by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) expert panel.
Expert Panel Reviews
Pathogenic
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
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
ClinVar reports other pathogenic variants at position 1306: L1306F
PM5 criterion applied.
Functional Summary
The BRCA1 L1306Dfs*23 variant is a truncating mutation that likely results in loss of BRCA1 protein function. Functional evidence indicates that truncating mutations in BRCA1 can lead to aberrant protein folding, impaired DNA damage response, and elevated levels of aneuploidy in human breast cancer cell lines. Additionally, mouse models with BRCA1 truncating mutations develop various cancers, supporting the damaging effect of this variant.
Database Previews
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 is: 'Very Strong Null variant (nonsense, frameshift, splice site) in a gene where loss of function is a known mechanism of disease.' The evidence for this variant shows: c.3916_3917del causes a frameshift (L1306Dfs*23) predicted to undergo nonsense-mediated decay and BRCA1 LOF is a known disease mechanism. Therefore, this criterion is applied at Very Strong strength because the variant is a null variant in a LOF gene.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: 'Strong Apply PS1 for predicted missense substitutions where a previously classified pathogenic variant causes the same amino acid change.' The evidence shows this variant is a frameshift, not a missense substitution. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for 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 information available for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to VCEP guidelines, the rule for PS3 is: 'Strong Well-established in vitro or in vivo functional studies supportive of a damaging effect.' The evidence shows: multiple functional studies of BRCA1 truncating variants demonstrate loss of protein function, impaired DNA damage response, and cancer phenotypes in models. Therefore, this criterion is applied at Strong strength because well-established functional assays support a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: 'Strong Prevalence of the variant in affected individuals is significantly increased compared to controls.' There are no published case-control data or odds ratios for this variant. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: 'Moderate or Strong Mutational hot spot or well‐studied functional domain without benign variation.' This variant is frameshift, not a missense in a 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 gnomAD.' The evidence shows: the variant is not present in gnomAD or other population databases. Therefore, this criterion is applied at Supporting strength because the variant is absent from controls.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: 'Supporting/Moderate/Strong for recessive disease when observed in trans with a pathogenic variant and phenotype consistent with BRCA1-related Fanconi Anemia.' There is no evidence of Fanconi Anemia phenotype or trans co-occurrence. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: 'Moderate Protein length changes due to in-frame deletions/insertions in non-repeat regions.' This variant is a frameshift, not in-frame. Therefore, this criterion is not applied.
PM5
PM5 (Moderate)
According to VCEP guidelines, the rule for PM5 is: 'Moderate Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before.' The evidence shows: this frameshift creates a PTC in exon 11, where multiple other pathogenic PTC variants are reported. Therefore, this criterion is applied at Moderate strength because it meets PTC recurrence in a known pathogenic context.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: 'Moderate Assumed de novo (without confirmation of paternity and maternity).' No de novo information is available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: 'Supporting/Moderate/Strong for co-segregation with disease in multiple affected family members.' No family segregation data are provided. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: 'Supporting Missense variant in a gene with low rate of benign missense variation.' This is a frameshift. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: 'Supporting Computational evidence of deleterious effect.' This variant is a frameshift and computational missense/splicing predictors are not applicable. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: 'Supporting Clinical phenotype highly specific for disease with single genetic etiology.' No specific clinical phenotype data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: 'Supporting Reputable source recently reports variant as pathogenic, but evidence not available for independent evaluation.' The evidence shows: ClinVar and ENIGMA expert panel report this variant as Pathogenic. Therefore, this criterion is applied at Supporting strength because multiple reputable sources classify it as pathogenic.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: 'Stand Alone allele frequency above 0.1% in controls.' The variant is absent from controls. 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 above 0.01% in controls.' The variant is absent from controls. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: 'Strong Applied in absence of recessive disease features.' Not evaluated; no Fanconi Anemia phenotype. Therefore, this criterion 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.' Functional studies show damaging effect. 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.' No segregation data showing lack of segregation. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP1 is: 'Supporting Missense variant outside functional domain.' This is a frameshift. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'Supporting Observed in trans with a pathogenic variant for dominant disorder.' No co-occurrence data are available. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'Supporting In-frame indels in repetitive regions.' This is a frameshift, not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: 'Supporting Computational evidence suggests no impact.' Not applicable for frameshift. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: 'Supporting Co-occurrence with pathogenic variants in other genes without specific phenotype.' No such data are available. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'Supporting Reputable source reports variant as benign.' No reputable benign reports exist. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: 'Supporting Silent variants or intronic outside splice sites with no impact.' This is a coding frameshift. Therefore, this criterion is not applied.