BRCA2 c.1238del, p.Leu413HisfsTer17
NM_000059.4:c.1238del
Pathogenic
This frameshift variant c.1238delT (L413Hfs*17) in BRCA2 introduces a premature stop codon resulting in loss of critical domains. It meets PVS1 (Very Strong LOF), PS3 (Strong functional impairment), and PP5 (Supporting clinical assertions), fulfilling ACMG criteria for a Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
PS3
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.1238del
Protein Change
L413Hfs*17
Location
Exon 10
(Exon 10 of 27)
5'Exon Structure (27 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 413: L413P
Variant interpretation based on transcript NM_000059.4
Genome Browser
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HGVS InputNM_000059:c.1238del
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ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.0004%
Extremely Rare
Highest in Population
European (non-Finnish)
0.000883%
Very Rare
Global: 0.0004%
European (non-Finnish): 0.000883%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 249956Alt: 1Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.0004%, 1/249956 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.000883%, 1/113268 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
8 publications
Pathogenic
Based on 16 submitter reviews in ClinVar
Submitter Breakdown
16 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (8)
Variant summary: BRCA2 c.1238delT (p.Leu413HisfsX17) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 249956 control chromosomes (gnomAD). c.1238delT has been reported in the literature and in at least one clinical database in multiple individuals and families affected with breast and/or ovarian cancer (e.g. Giannini_2006, Caux-Moncoutier_2011, Manie_2016, Coppa_2014, Tedaldi_2020, BIC database). 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. Nine submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
The c.1238delT pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 1238, causing a translational frameshift with a predicted alternate stop codon (p.L413Hfs*17). This alteration has been identified in numerous Italian families with bilateral breast cancer, male breast cancer, and ovarian cancer histories (Capalbo C et al. Ann. Oncol., 2006 Jun;17 Suppl 7:vii34-40; Giannini G et al. Breast Cancer Res Treat, 2006 Nov;100:83-91; Minucci A et al. Expert Rev Mol Diagn, 2015 Aug;15:1383-403; Fanale D et al. Cancers (Basel), 2020 Aug;12(9); Incorvaia L et al. Cancers (Basel), 2020 May;12(5)). 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.Leu413Hisfs*17) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with a personal and/or family history of breast cancer (PMID: 16760289, 21120943, 26306726). This variant is also known as 1466delT. ClinVar contains an entry for this variant (Variation ID: 37731). For these reasons, this variant has been classified as Pathogenic.
PM5_strong, PVS1
The BRCA2 c.1238delT (p.Leu413HisfsTer17) variant results in a frameshift, and is predicted to result in premature termination of the protein. The p.Leu413HisfsTer17 has been reported in eight studies in which it has been identified in a heterozygous state in at least 11 individuals with hereditary cancer, either breast cancer, breast cancer and ovarian cancer or ovarian cancer alone (Capalbo et al. 2006; Giannini et al. 2006; Caux-Moncoutier et al. 2011; Concolino et al.2014; Coppa et al. 2014; Minucci 2015; Manie et al. 2016; Palmero et al. 2018). The variant is reported at a frequency of 0.000009 in the European (non-Finnish) population from the Genome Aggregation Database but this is based on one allele in a region of good sequencing coverage, so the variant is presumed to be rare. Although the c.3201+1G>C variant has not been reported in the literature in individuals with Fanconi anemia, it cannot be ruled out of causing this condition based on allele frequency in consideration of condition penetrance and prevalence estimates. Based on the evidence and the potential impact of frameshift variants, the BRCA2 p.Leu413HisfsTer17 variant is classified as pathogenic for hereditary breast and ovarian cancer. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (16 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 413: L413P
PM5 criterion applied.
Functional Summary
The BRCA2 L413Hfs*17 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 evidence indicates that such truncating mutations impair the nuclear localization of BRCA2, which is essential for its role in maintaining 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
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 2.07
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: NM_000059.4:c.1238delT causes a frameshift leading to a premature stop (L413Hfs*17), predicting LOF in BRCA2. Therefore, this criterion is applied at Very Strong strength because the variant is a null variant in BRCA2, where LOF is a known disease mechanism.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "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)." 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, the rule 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 status or parental testing data are available. 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 shows: functional assays demonstrate that L413Hfs*17 truncation abolishes nuclear localization and impairs homologous recombination. 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: The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls, with p-value ≤0.05 and OR ≥4." 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, the rule for PM1 is: "Moderate: Variants located in a (potentially) clinically important functional domain (e.g., PALB2 binding aa 10–40; DNA binding aa 2481–3186)." The evidence for this variant shows: L413Hfs*17 lies outside these domains. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting: Absent from controls in an outbred population (gnomAD v2.1/v3.1)." The evidence for this variant shows: it is present in gnomAD at MAF=0.0004%. Therefore, this criterion is not applied because the variant is not absent from controls.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: "Apply for patient with phenotype consistent with BRCA-related Fanconi Anemia and co-occurring variants in the same gene." The evidence for this variant shows: no Fanconi Anemia phenotype or compound heterozygosity data are available. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes as a result of in-frame deletions/insertions in a non-repetitive region or stop-loss variants." The evidence for this variant shows: it is a frameshift leading to truncation, not an in-frame change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5_PTC 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: no data that another PTC has been reported in the same exon. 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/or maternity." The evidence for this variant shows: no parental data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Supporting/Moderate/Strong: Co-segregation with disease in multiple affected family members, based on LR thresholds." The evidence for this variant shows: no segregation data. 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 and where missense variants are a common mechanism of disease." 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, the rule for PP3 is: "Supporting: In silico predictions of deleterious effect for missense/in-frame or splicing variants." The evidence for this variant shows: it is a frameshift and in silico tools are not applied. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: "Supporting/Moderate/Strong: Specific phenotype or family history highly specific for a disease with a single genetic etiology." The evidence for this variant shows: no detailed phenotype or multifactorial data. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source recently reports variant as pathogenic, but the evidence is not available for independent evaluation." The evidence for this variant shows: ClinVar (16 labs) and ENIGMA report 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: Filter allele frequency >0.1% in gnomAD non-cancer populations." The evidence for this variant shows: MAF=0.0004%, below threshold. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong: Filter allele frequency >0.01% in gnomAD non-cancer populations." The evidence for this variant shows: MAF=0.0004%, below threshold. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Applied in absence of recessive disease features (Fanconi Anemia) with point-based absence scoring." The evidence for this variant shows: no FA phenotype data. 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." The evidence for this variant shows: functional studies demonstrate a 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 family members (LR ≤0.05)." 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, the rule for BP1 is: "Strong: Silent or missense/in-frame variant outside functional domains with no splicing predicted." The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observation in trans with a pathogenic variant for a recessive disorder unrelated to phenotype." The evidence for this variant shows: no data on in trans observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame indels in repetitive regions without a known function." The evidence for this variant shows: it is a frameshift, not an in-frame indel 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: In silico predictions indicate no impact on protein or splicing for missense/in-frame/silent variants in specified domains." 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, the rule for BP5 is: "Supporting: Variant observed in a case with an alternate molecular basis for disease." 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 for BP6 is: "Reputable source reports variant as benign, but evidence not available." The evidence for this variant shows: no such benign assertions. 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 variants predicted to have no impact on splicing located outside conserved splice sites." The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.