BRCA2 c.3847_3848del, p.Val1283LysfsTer2
NM_000059.4:c.3847_3848del
COSMIC ID: COSM7345505
Pathogenic
c.3847_3848del (p.V1283Kfs*2) in BRCA2 is classified as Pathogenic based on Very Strong PVS1 and Strong PS3 supporting LOF and functional impairment, with Supporting BS1 reflecting low population frequency.
ACMG/AMP Criteria Applied
PVS1
PS3
BS1
Genetic Information
Gene & Transcript Details
Gene
BRCA2
Transcript
NM_000059.4
MANE Select
Total Exons
27
Strand
Forward (+)
Reference Sequence
NC_000013.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000059.2 | Alternative | 27 exons | Forward |
| NM_000059.3 | RefSeq Select | 27 exons | Forward |
Variant Details
HGVS Notation
NM_000059.4:c.3847_3848del
Protein Change
V1283Kfs*2
Location
Exon 11
(Exon 11 of 27)
5'Exon Structure (27 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 1283: V1283L, V1283I, V1283A
Alternate Identifiers
COSM7345505
Variant interpretation based on transcript NM_000059.4
Genome Browser
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HGVS InputNM_000059:c.3847_3848del
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00509%
Rare
Highest in Population
European (non-Finnish)
0.00982%
Rare
Global: 0.00509%
European (non-Finnish): 0.00982%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 235838Alt: 12Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00509%, 12/235838 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.00982%, 11/112032 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
12 publications
Pathogenic
Based on 46 submitter reviews in ClinVar
Submitter Breakdown
46 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (12)
The p.Val1283LysfsX2 variant in BRCA2 has been reported in >35 individuals with BRCA2-associated cancers (Wang 2012 PMID:21643751, Breast Cancer Information Core (BIC) database: https://research.nhgri.nih.gov/bic/). This variant has also been identified in 0.013% (9/67984) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v3.1.2). This frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1283 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism for HBOC. Additionally, this variant was classified as pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID 37859). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the predicted impact to the protein. ACMG/AMP criteria applied: PS4, PM2_Supporting, PVS1.
The c.3847_3848delGT (p.V1283Kfs*2) alteration, located in exon 11 (coding exon 10) of the BRCA2 gene, consists of a deletion of 2 nucleotides from position 3847 to 3848, causing a translational frameshift with a predicted alternate stop codon after 2 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this allele has an overall frequency of 0.005% (12/235838) total alleles studied. The highest observed frequency was 0.01% (11/112032) of European (non-Finnish) alleles. This mutation has been detected in numerous families with breast, ovarian, pancreatic, and/or prostate cancer (Tavtigian, 1996; Hahn, 2003; Janaviius, 2010; Zhang, 2011; Kote-Jarai, 2011; Meisel, 2017; El Ansari, 2020; Heramb, 2018). This mutation was also reported in one family diagnosed with familial colorectal cancer type X (FCCX) that had no alteration detected in the mismatch repair (MMR) pathway (Garre, 2015). This variant has been identified in conjunction with another BRCA2 variant in an individual with features consistent with Fanconi anemia (McReynolds, 2021). Of note, this alteration is also designated as 4075delGT in published literature. Based on the available evidence, this alteration is classified as pathogenic.
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
Variant summary: This frameshift variant leads to premature truncation at exon 11. In ExAC, it has been observed at allele frequency of 11/94102 chromosomes. This frequency is lower than the maximal expected allele frequency for a pathogenic BRCA2 variant based on the disease prevalence of HBOC. It has been recurrently observed in patients with HBOC. This supports that the 11 individuals with this variant in ExAC are very likely to represent as subclinical cases and/or reduced penetrance. Multiple labs (via ClinVar) classify the variant as pathogenic. Therefore, based on the variant's nature and location, and population and patient data, this has been classified as Pathogenic.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (46 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 1283: V1283L, V1283I, V1283A
PM5 criterion applied.
Functional Summary
The BRCA2 V1283Kfs*2 variant is a truncating mutation that results in the loss of critical protein domains, including the C-terminal DNA binding domain, nuclear localization signal, and CDK2 phosphorylation site. Experimental studies have demonstrated that such truncating mutations impair the nuclear localization of BRCA2, which is essential for its normal function in maintaining the integrity of homologous recombination during the DNA damage response. This functional impairment supports a damaging effect of the variant.
Database Previews
OncoKB
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, PVS1 rule: "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: c.3847_3848del causes a frameshift leading to a premature stop and loss of critical BRCA2 domains, and it is not in the last exon. Therefore, this criterion is applied at Very Strong strength because this null variant meets PVS1 per the VCEP flowchart.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 rule: "Strong Apply PS1 for predicted missense substitutions, where a previously classified pathogenic variant is considered to act via protein change." The evidence for this variant shows: it is a frameshift, not a missense substitution. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 rule: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to VCEP guidelines, PS3 rule: "Strong Well-established in vitro or in vivo functional studies supportive of a damaging effect." The evidence for this variant shows: experimental studies demonstrate impaired nuclear localization and homologous recombination function due to truncation of BRCA2. Therefore, this criterion is applied at Strong strength because these functional assays directly support damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 rule: "Strong The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls." The evidence for this variant shows: no case-control or prevalence data in affected individuals. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, PM1 rule: "Moderate Applies to variants located in a mutational hotspot or functional domain without benign variation." The evidence for this variant shows: it is a frameshift outside defined mutational hotspots or domains. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, PM2 rule: "Supporting Absent from controls in an outbred population." The evidence for this variant shows: it is present in gnomAD with MAF=0.00509%. Therefore, this criterion is not applied.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, PM3 rule: "Supporting Apply for patient with phenotype consistent with BRCA1- or BRCA2-related Fanconi Anemia (FA) and co-occurrent variants." The evidence for this variant shows: no Fanconi Anemia phenotype or co-occurring variant data. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, PM4 rule: "Moderate Protein length changes due to in-frame indels or stop-loss variants." The evidence for this variant shows: it is a frameshift leading to truncation, not an in-frame indel or stop-loss. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, PM5 rule: "Strong Protein termination codon (PTC) variant in an exon where a different proven pathogenic PTC variant has been seen before." The evidence for this variant shows: no data on other PTCs in the same exon. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 rule: "Assumed de novo, without confirmation of paternity/maternity." The evidence for this variant shows: no de novo or parental data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 rule: "Supporting 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 VCEP guidelines, PP2 rule: "Supporting Missense variant in a gene with low benign variation and where missense is common." The evidence for this variant shows: it is a frameshift, not a missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3 rule: "Supporting In silico predictions supportive of a deleterious effect." The evidence for this variant shows: it is a frameshift and SpliceAI scores all zero; in silico tools for missense are not applicable. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, PP4 rule: "Supporting Phenotype is highly specific for a disease with a single genetic etiology." The evidence for this variant shows: no specific clinical phenotype data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 rule: "Reputable source recently reports variant as pathogenic, but evidence is not available to the laboratory." The evidence for this variant shows: although ClinVar lists it as pathogenic, VCEP discourages reliance on PP5. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 rule: "Stand Alone Filter allele frequency is above 0.1%." The evidence for this variant shows: MAF=0.00509%, which is below the BA1 threshold. Therefore, this criterion is not applied.
BS1
BS1 (Supporting) Strength Modified
According to VCEP guidelines, BS1 rule: "Supporting Filter allele frequency (FAF) is above 0.002% and <=0.01%." The evidence for this variant shows: MAF=0.00509% in gnomAD. Therefore, this criterion is applied at Supporting strength because the frequency meets the VCEP-defined benign threshold.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 rule: "Strong Applied in absence of features of recessive disease, namely Fanconi Anemia phenotype." The evidence for this variant shows: no clinical data to exclude Fanconi Anemia features. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 rule: "Strong Well-established in vitro or in vivo functional studies shows no damaging effect on protein function." The evidence for this variant shows: functional studies demonstrate damaging effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 rule: "Strong Lack of segregation in affected members of a family." 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, BP1 rule: "Strong Silent substitution, missense or in-frame indels outside a functional domain." The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, BP2 rule: "Strong Observed in cis with a pathogenic variant or in trans for recessive disorder." The evidence for this variant shows: no data on cis/trans observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to VCEP guidelines, BP3 rule: "Supporting In-frame deletions in a repetitive region." The evidence for this variant shows: it is a frameshift outside a repetitive region. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, BP4 rule: "Supporting Missense or in-frame variants inside a domain with no predicted impact." The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, BP5 rule: "Supporting Observation in a case with another pathogenic variant in a different gene." The evidence for this variant shows: no such co-occurrence data. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 rule: "Reputable source reports variant as benign, but evidence is not available." The evidence for this variant shows: no reputable benign reports. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 rule: "Supporting Silent variants with no predicted splicing impact." The evidence for this variant shows: it is a frameshift, not a silent variant. Therefore, this criterion is not applied.