BRCA2 c.714_716dup, p.Glu238_Ser239insArg
NM_000059.4:c.714_716dup
Variant of Uncertain Significance (VUS)
This variant remains a VUS based on one Moderate pathogenic criterion (PM4) and one Supporting pathogenic criterion (PM2) balanced by a Strong benign criterion (BP1); evidence is insufficient to classify as either Pathogenic or Benign.
ACMG/AMP Criteria Applied
PM2
PM4
BP1
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.714_716dup
Protein Change
E238_S239insR
Location
Exon 9
(Exon 9 of 27)
5'Exon Structure (27 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_000059.4
Genome Browser
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HGVS InputNM_000059:c.714_716dup
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000798%
Very Rare
Highest in Population
European (non-Finnish)
0.00177%
Rare
Global: 0.000798%
European (non-Finnish): 0.00177%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 250512Alt: 2Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000798%, 2/250512 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.00177%, 2/113296 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
5 publications
Uncertain Significance (VUS)
Based on 11 submitter reviews in ClinVar
Submitter Breakdown
10 VUS
1 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (5)
Variant summary: BRCA2 c.714_716dupAAG (p.Glu238_Ser239insArg) results in an in-frame insertion that is predicted to insert one amino acids into the encoded protein. The variant allele was found at a frequency of 8e-06 in 250512 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.714_716dupAAG has been reported in the literature in individuals affected with ovarian cancer and colorectal cancer (Alsop_2012, Hansen_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
This variant causes an in-frame insertion of one amino acid at exon 9 of the BRCA2 protein. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with colorectal cancer (PMID: 28195393). This variant has also been identified in 2/250512 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
The c.714_716dupAAG variant (also known as p.E238_S239insR), located in coding exon 8 of the BRCA2 gene, results from an in-frame duplication of AAG at nucleotide positions 714 to 716. This results in the insertion of an extra arginine residue between codons 238 and 239. This alteration was identified in an individual diagnosed with colorectal cancer (Hansen MF et al, Clin. Genet. 2017 Oct;92:405-414). Of note, this alteration is also designated as designated as c.713_714insAAG in published literature. This amino acid region is not well conserved in available vertebrate species. In addition, this alteration is predicted to be inconclusive by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the available evidence, the clinical significance of this variant remains unclear.
The BRCA2 c.714_716dup (p.Glu238_Ser239insArg) variant has been reported in the published literature in reportedly healthy individuals (PMID: 24728327 (2014)). It has also been identified in individuals with familial colorectal cancer (PMID: 28195393 (2017)) and ovarian cancer (PMID: 22711857 (2012)). The frequency of this variant in the general population, 0.000008 (2/250512 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.
This variant, c.714_716dup, results in the insertion of 1 amino acid(s) of the BRCA2 protein (p.Glu238_Ser239insArg), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs587778130, gnomAD 0.002%). This variant has been observed in individual(s) with colon cancer and ovarian cancer (PMID: 22711857, 28195393). This variant is also known as c.716_717het insAAG. ClinVar contains an entry for this variant (Variation ID: 126202). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (10 clinical laboratories) and as Uncertain Significance (2 clinical laboratories) and as Likely benign (1 clinical laboratories).
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
Functional Summary
The BRCA2 E238_S239insR variant has not been functionally characterized, and its biological significance remains unknown.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 1.28
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
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 is a known mechanism of disease." The evidence for this variant shows an in-frame insertion (E238_S239insR), not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Strong: Predicted missense substitutions where a previously classified pathogenic variant is considered to act via protein change (no confirmed or predicted effect on mRNA splicing)." The evidence for this variant shows an in-frame insertion, not a missense substitution matching a known pathogenic change. 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." No parental testing or de novo evidence is available for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: "Strong well-established in vitro or in vivo functional studies supportive of a damaging effect." No functional studies have been performed for this variant. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Strong: The prevalence of the variant in affected individuals is significantly increased compared to controls (OR ≥4, p ≤0.05)." There are no case-control data or evidence of increased prevalence in affected individuals. 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 mutational hotspot or functional domain (BRCA2 PALB2 binding aa 10-40; DNA binding aa 2481-3186)." The variant at aa238-239 lies outside these defined domains. 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 v2.1 and v3.1 (non-cancer, exome)." The evidence for this variant shows a MAF of 0.000798% (2/250512 alleles) in gnomAD with no homozygotes. Therefore, this criterion is applied at Supporting strength because the variant is extremely rare or absent in controls.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3_Supporting is: "Apply for patient with Fanconi Anemia phenotype and co-occurring variants in the same gene." No Fanconi Anemia phenotype or compound heterozygosity data are available. Therefore, this criterion is not applied.
PM4
PM4 (Moderate)
According to standard ACMG guidelines, the rule for PM4 is: "Moderate: Protein length changes due to in-frame deletion/insertion in a non-repeat region or stop-loss." The evidence for this variant shows an in-frame insertion of one amino acid (Arg) outside of a repeat region. Therefore, this criterion is applied at Moderate strength because the variant alters protein length.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different missense change is pathogenic." This variant is an in-frame insertion, not a missense substitution at a residue with known pathogenic variants. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity." No de novo or parental data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Supporting to Strong: Co-segregation with disease in multiple affected family members (Bayes Score LR ≥2.08:1 for Supporting)." No family segregation data are available. 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 (<10%) and missense variants are a common mechanism of disease." BRCA2 does not meet this low benign missense rate criterion and the variant is an in-frame insertion. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Supporting: Predicted impact via protein change (BayesDel no-AF ≥0.30) or splicing (SpliceAI ≥0.2) for in-frame or silent variants inside a functional domain." The variant is outside defined functional domains and SpliceAI predicts minimal impact (0.03). Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: "Supporting to Strong: Phenotype specificity based on multifactorial likelihood data for breast cancer (LR ≥2.08:1 for Supporting)." No multifactorial likelihood or phenotype specificity data are available. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Supporting: Reputable source reports variant as pathogenic." ClinVar submissions report this variant only as VUS or Likely Benign, not Pathogenic. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone: Filter allele frequency (FAF) >0.001 (0.1%) in gnomAD." The evidence for this variant shows FAF 0.00000798 (<0.001). Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong: FAF >0.0001 (0.01%) in gnomAD." The evidence for this variant shows FAF 0.00000798 (<0.0001). Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Supporting to Strong: Observed in healthy adults in absence of Fanconi Anemia phenotype (≥1 point for Supporting)." No data on healthy adult carriers are available. 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 on protein function." No functional studies exist for this variant. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: "Supporting to Strong: Lack of segregation in affected family members (Bayes Score LR ≤0.48:1 for Supporting)." No segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Strong) Strength Modified
According to VCEP guidelines, the rule for BP1_Strong is: "Apply BP1_Strong for silent substitution, missense or in-frame insertion, deletion or delins variants outside a clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1)." The evidence for this variant shows an in-frame insertion at aa238-239 (outside domains aa10-40 and aa2481-3186) and SpliceAI predicts no splicing impact (0.03). Therefore, this criterion is applied at Strong strength.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Supporting: Observed in cis with a pathogenic variant in a gene for dominant disorder." No co-occurrence with a pathogenic variant is reported. 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 deletion/insertion in a repetitive region without a known function." There is no evidence that this variant is in a repetitive region. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Supporting: Computational evidence predicts no impact for missense/in-frame variants inside a functional domain (BayesDel no-AF ≤0.18 and SpliceAI ≤0.1)." The variant lies outside functional domains, so BP4 does not apply under VCEP. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: "Supporting to Strong: Co-observation with pathogenic variant based on multifactorial clinical data." No such co-observation 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." There are no reputable benign assertions beyond a single Likely Benign in ClinVar, which is insufficient. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting: Silent or intronic variant outside splice sites with no splicing impact." This is an in-frame insertion, not a silent or intronic variant. Therefore, this criterion is not applied.