BRCA2 c.3847_3848del, p.Val1283LysfsTer2
NM_000059.4:c.3847_3848del
COSMIC ID: COSM7345505
Pathogenic
This frameshift variant introduces a premature stop codon causing loss of function in BRCA2, meeting PVS1 (Very Strong) and supported by functional evidence (PS3 Strong), rarity in controls (PM2 Supporting), presence of other PTCs in the same exon (PM5 Supporting), and multiple reputable pathogenic reports (PP5 Supporting). Combined evidence meets ACMG criteria for Pathogenic.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
PM5
PP5
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 likely results in loss of function. Functional evidence indicates that truncating mutations in BRCA2 impair nuclear localization and disrupt the DNA damage response, essential for maintaining genomic integrity. This variant is associated with an increased risk of developing various cancers, supporting its damaging effect.
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, 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 a frameshift (c.3847_3848delGT) introducing a premature stop codon in BRCA2, a gene where LOF is a known disease mechanism. Therefore, this criterion is applied at Very Strong strength because the variant is a null frameshift in a LOF gene.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 applies to predicted missense substitutions where a previously classified pathogenic variant causes the same amino acid change. The evidence for this variant shows: it is a frameshift leading to truncation, 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: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence shows: there is no information on de novo occurrence. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to VCEP guidelines, PS3 is: "Well-established in vitro or in vivo functional studies supportive of a damaging effect." The evidence for this variant shows: functional assays demonstrate that truncating BRCA2 variants impair nuclear localization and DNA damage response, supporting a damaging effect. Therefore, this criterion is applied at Strong strength.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 is: "The prevalence of the variant in affected individuals is significantly increased compared to controls (p ≤ 0.05 and OR ≥ 4)." The evidence shows: no case-control data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot and/or critical and well-established functional domain without benign variation." The evidence shows: this variant's location is not reported in a defined hotspot or critical domain. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, PM2 is: "Absent from controls in an outbred population (gnomAD non-cancer)." The evidence for this variant shows: MAF ≈ 0.00509% (12/235,838 alleles) in gnomAD, which is sufficiently rare. Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, PM3 applies to biallelic variants in BRCA2-related Fanconi Anemia with co-occurrence of a second variant. The evidence shows: no Fanconi Anemia phenotype or second variant reported. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, PM4 is: "Protein length changes due to in-frame indels or stop-loss variants not resulting in LOF." The evidence shows: this variant causes LOF via frameshift and is covered by PVS1. Therefore, this criterion is not applied.
PM5
PM5 (Supporting) Strength Modified
According to VCEP guidelines, PM5 is: "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: it is a novel frameshift resulting in a PTC at codon 1284 and other PTC variants have been reported in this exon. Therefore, this criterion is applied at Supporting strength.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, without confirmation of paternity and maternity." The evidence shows: no data on de novo status. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 applies to co-segregation with disease in multiple affected family members. The evidence shows: no segregation data available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation." The evidence shows: this is a frameshift variant, not missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3 applies to missense or in-frame indels in functional domains with computational evidence. The evidence shows: this variant is a frameshift and computational tools (SpliceAI) predict no impact on splicing. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, PP4 applies to a highly specific phenotype or family history. The evidence shows: no phenotype or family history information provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, PP5 is: "Reputable source recently reports variant as pathogenic, but evidence is not available for independent evaluation." The evidence for this variant shows: ClinVar (46 submitters) and ENIGMA report it as Pathogenic. Therefore, this criterion is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 is: "Filter allele frequency (FAF) >0.1% in gnomAD." The evidence shows: frequency 0.00509% <0.1%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 is: "Filter allele frequency (FAF) >0.01% in gnomAD." The evidence shows: frequency 0.00509% <0.01%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 applies to absence of phenotype in homozygotes indicating benign. The evidence shows: no phenotype data for homozygotes. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 applies when functional studies show no damaging effect. The evidence shows: functional assays demonstrate a damaging effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 applies to lack of segregation in affected family members. The evidence shows: no segregation data available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines, BP1 applies to silent or missense variants outside functional domains without splicing impact. The evidence shows: variant is a frameshift. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies when a variant is observed in cis/trans with a pathogenic variant in unaffected individuals. The evidence shows: no such observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions without known function. The evidence shows: 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, BP4 applies to computational evidence supporting no impact (BayesDel ≤0.18 and SpliceAI ≤0.1). The evidence shows: variant is frameshift and SpliceAI predicts no splicing impact, but BP4 is reserved for missense/in-frame/intronic. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, BP5 applies when a variant is observed in a case with an alternate molecular diagnosis. The evidence shows: no such co-occurrence data. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 applies when a reputable source reports a variant as benign without evidence. The evidence shows: no reputable benign reports. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 applies to silent or intronic variants outside splice sites with no impact. The evidence shows: variant is a frameshift. Therefore, this criterion is not applied.