BRCA1 c.3916_3917del, p.Leu1306AspfsTer23
NM_007294.4:c.3916_3917del
Pathogenic
This frameshift variant causes a premature stop codon in BRCA1 (L1306Dfs*23), meeting PVS1 (Very Strong), PS3 (Strong), PM2 (Supporting), PM5 (Supporting), and PP5 (Supporting), which together justify a Pathogenic classification.
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
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
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
OncoKB
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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 (+/−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 a frameshift leading to a premature stop (L1306Dfs*23) in BRCA1, a gene where LOF is a known mechanism. Therefore, this criterion is applied at Very Strong strength because it is a null variant in BRCA1 leading to loss of function.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "Strong: same amino acid change as a previously established pathogenic variant." The evidence for this variant shows a frameshift, not a missense change identical to a known pathogenic variant. 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)." No de novo status or parental testing data are 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 for this variant includes functional data showing truncating BRCA1 variants disrupt DNA damage response and cause cancer phenotypes. Therefore, this criterion is applied at Strong strength because well-established functional studies support a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Strong: prevalence in affected individuals significantly increased compared to controls (case-control data, OR≥4 with p≤0.05)." No case-control data are provided 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: variant located in a (potentially) clinically important functional domain without benign variation." This is a frameshift variant, not a missense in a defined 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 (gnomAD)." The evidence shows the variant is absent from gnomAD. Therefore, this criterion is applied at Supporting strength because it is absent from population databases.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: "Supporting: detected in trans with a pathogenic variant in patients with Fanconi Anemia phenotype." No Fanconi Anemia clinical or in trans data are provided. 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 indels or stop-loss variants." This variant causes a frameshift with premature stop and is already covered by PVS1. Therefore, this criterion is not applied.
PM5
PM5 (Supporting) 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 before." The evidence shows L1306Dfs*23 is a PTC and other truncating pathogenic variants occur in this region. Therefore, this criterion is applied at Supporting strength because it is a novel PTC in an exon with known pathogenic PTCs.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Moderate: assumed de novo without confirmation of paternity/maternity." No de novo assumption data are provided. 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." No 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 in a gene with low rate of benign missense variation." This is a frameshift variant, not a missense substitution. 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 (BayesDel ≥0.28 or SpliceAI ≥0.2)." SpliceAI score is 0.11 and no in silico consensus for a damaging missense. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: "Supporting: combined multifactorial likelihood clinical data for breast cancer." No multifactorial clinical 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 (e.g. ClinVar expert panel) reports variant as pathogenic without available evidence." The evidence shows ClinVar and ENIGMA classify this variant as pathogenic. Therefore, this criterion is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone: allele frequency >0.1%." The variant is absent from population databases. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong: allele frequency >0.01%." The variant is absent from population databases. 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 (Fanconi Anemia)." No FA phenotype or proband count is provided. 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 for this variant 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 members." No segregation data are provided. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP1 is: "Strong: silent or in-frame variants outside functional domains with no splicing effect." This is a frameshift variant. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Moderate: observed in trans with a pathogenic variant for a fully penetrant dominant gene." No such co-occurrence data are provided. 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 variant. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Supporting: computational evidence against impact (BayesDel ≤0.15 and SpliceAI ≤0.1)." SpliceAI is 0.11 but variant is a frameshift PTC. 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 variant in another gene with no specific phenotype." No such data are provided. 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 without evidence." No such source reports benign. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Supporting: silent changes or intronic variants with no splicing impact." This variant is a frameshift. Therefore, this criterion is not applied.