BRCA2 c.6724_6725del, p.Asp2242PhefsTer2
NM_000059.4:c.6724_6725del
COSMIC ID: COSM10177260
Pathogenic
c.6724_6725del (D2242Ffs*2) is a BRCA2 frameshift variant leading to LOF in a gene where LOF is pathogenic. VCEP PVS1 Very Strong, PS3 Strong, and PM2 Supporting criteria are met, supporting a Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
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.6724_6725del
Protein Change
D2242Ffs*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 2242: D2242N, D2242G, D2242E
Alternate Identifiers
COSM10177260
Variant interpretation based on transcript NM_000059.4
Genome Browser
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HGVS InputNM_000059:c.6724_6725del
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Clinical Data
Global Frequency
0.000398%
Extremely Rare
Highest in Population
Admixed American
0.00289%
Rare
Global: 0.000398%
Admixed American: 0.00289%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 251336Alt: 1Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000398%, 1/251336 alleles, homozygotes = 0) and at a higher frequency in the Admixed American population (MAF= 0.00289%, 1/34580 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
6 publications
Pathogenic
Based on 12 submitter reviews in ClinVar
Submitter Breakdown
12 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (6)
This variant deletes 2 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. 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 and in high-risk breast and ovarian cancer families (PMID: 19656164, 22217648, 22382806, 22798144, 25863477, 26187060, 27836010, doi:10.21203/rs.3.rs-734551/v1), and has also been identified in 6 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). This variant has been identified in 1/251336 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
This sequence change creates a premature translational stop signal (p.Asp2242Phefs*2) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs397507375, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 19656164, 22217648, 22382806, 22798144, 25863477). This variant is also known as 6952delGA. ClinVar contains an entry for this variant (Variation ID: 38062). For these reasons, this variant has been classified as Pathogenic.
The c.6724_6725delGA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 6724 to 6725, causing a translational frameshift with a predicted alternate stop codon (p.D2242Ffs*2). This variant was reported in individual(s) with features consistent with BRCA2-related cancer predisposition (Kwong A et al. J Med Genet. 2016 Jan;53:15-23; Rebbeck TR et al. Hum. Mutat. 2018 May;39:593-620; Ryu JM et al. Breast Cancer Res Treat. 2019 Jan;173:385-395). 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 variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. Additionally, this variant has been reported in an individual with breast cancer in the published literature (PMID: 19656164 (2009)). Based on the available information, this variant is classified as pathogenic.
Variant summary: BRCA2 c.6724_6725delGA (p.Asp2242PhefsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251336 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6724_6725delGA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g., Kang_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication was ascertained in the context of this evaluation (PMID: 25863477). Seven ClinVar submitters (evaluation after 2014) have cited the variant, and all submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (12 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 2242: D2242N, D2242G, D2242E
PM5 criterion applied.
Functional Summary
The BRCA2 D2242Ffs*2 variant is a truncating mutation that likely results in loss of function. Functional studies indicate that truncating mutations in BRCA2 impair nuclear localization, which is essential for its role in the DNA damage response. This disruption affects the integrity of homologous recombination, a critical process for DNA repair. Consequently, such mutations are associated with an increased risk of developing various cancers, including breast, ovarian, prostate, and pancreatic cancers.
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/finding for PVS1 is: "**Very Strong Strength**: 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. Apply at appropriate strength according to PVS1 flowchart...". The evidence for this variant shows: c.6724_6725del (D2242Ffs*2) is a frameshift predicted to create a premature termination codon in BRCA2, a gene where LOF is a known mechanism of disease and the variant is not in the last exon. Therefore, this criterion is applied at Very Strong strength because it is a null variant in a gene where LOF causes disease.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for PS1 is: "**Strong Strength**: Strong Apply PS1 for predicted missense substitutions where a previously classified pathogenic variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing (SpliceAI≤0.1))." The evidence for this variant shows: c.6724_6725del is a frameshift variant, not a missense substitution. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PS2 is: "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 information is available. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to VCEP guidelines, the rule/finding for PS3 is: "**Strong Strength**: Strong Well-established in vitro or in vivo functional studies supportive of a damaging effect. Apply PS3 for assays measuring effect via protein only OR mRNA and protein combined." The evidence for this variant shows: functional studies indicate truncating BRCA2 mutations impair nuclear localization and homologous recombination. Therefore, this criterion is applied at Strong strength because well-established functional data support a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for PS4 is: "**Strong Strength**: Strong The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Case-control studies; p-value ≤0.05 and OR ≥4 (lower confidence interval excludes 2.0)." The evidence for this variant shows: no case-control data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, PM1 applies to: "Variants located in a (potentially) clinically important functional domain defined for BRCA2." The evidence for this variant shows: it is a truncating variant, not evaluated by domain-based criteria. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule/finding for PM2 is: "**Supporting Strength**: Supporting 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: MAF = 0.000398% in gnomAD, extremely rare. Therefore, this criterion is applied at Supporting strength because the variant is absent or at extremely low frequency in controls.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, PM3 applies to: "Variants observed in trans with a pathogenic variant in BRCA1/2-related Fanconi Anemia phenotype with phenotype-specific points." The evidence for this variant shows: no biallelic or FA phenotype data available. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PM4 is: "Protein length changes as a result of in-frame deletions/insertions in a non-repeat region or stop-loss variants." The evidence for this variant shows: this is a frameshift/truncating variant covered under PVS1. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for PM5 is: "**Strong Strength**: 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 are available demonstrating another PTC in the same exon. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity." The evidence for this variant shows: no de novo information is available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for PP1 is: "Co-segregation with disease in multiple affected family members in BRCA2, as measured by a quantitative co-segregation analysis." The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease." The evidence for this variant shows: this is a frameshift variant, not missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for PP3 is: "Supporting predicted splicing impact (SpliceAI ≥0.2) or protein impact (BayesDel no-AF ≥0.30) for missense/in-frame variants in functional domains." The evidence for this variant shows: frameshift variants are not evaluated by in silico predictors. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for PP4 is: "Use of specific patient phenotype/family history likelihood ratios for BRCA2-related cancer phenotypes." The evidence for this variant shows: individual clinical phenotype data are not provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for PP5 is: "Reputable source reports variant as pathogenic, but evidence is not available for independent evaluation." The evidence for this variant shows: although ClinVar and ENIGMA report pathogenicity, PP5 is discouraged by VCEP. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for BA1 is: "Stand Alone filter allele frequency (FAF) >0.001 in gnomAD non-cancer populations." The evidence for this variant shows: MAF = 0.000398%, below threshold. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for BS1 is: "Strong FAF >0.0001 and ≤0.001; Supporting FAF >0.00002 and ≤0.0001 in gnomAD non-cancer populations." The evidence for this variant shows: MAF = 0.000398%, below strong threshold and above supporting but not used for BS1. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for BS2 is: "Observed in healthy individuals without Fanconi Anemia features, with points-based system." The evidence for this variant shows: no data on FA phenotype in healthy adults. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for BS3 is: "Strong Well-established functional studies show 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, the rule/finding for BS4 is: "Strong Lack of segregation in affected members as measured by Bayes Score ≤0.05." The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for BP1 is: "Strong for silent or missense variants outside functional domains without splicing impact." The evidence for this variant shows: it is a truncating variant, not silent or missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP2 is: "Observed in trans with a pathogenic variant for a fully penetrant autosomal dominant gene." The evidence for this variant shows: no data on co-occurrence. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP3 is: "In-frame indels in repetitive region without a known function." The evidence for this variant shows: it is a frameshift variant, not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for BP4 is: "Supporting no predicted impact via protein or splicing for missense/in-frame variants inside functional domains." The evidence for this variant shows: it is a frameshift, not suitable for computational benign prediction. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for BP5 is: "Use to capture LR against pathogenicity based on multifactorial data for co-observed variants in different cancer genes." The evidence for this variant shows: no such co-observation data. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule/finding for BP6 is: "Reputable source reports variant as benign, but evidence is not available." The evidence for this variant shows: no reputable benign report. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule/finding for BP7 is: "Supporting for silent or intronic variants outside splice sites with no predicted impact." The evidence for this variant shows: it is a frameshift variant, not silent or intronic. Therefore, this criterion is not applied.