13-32333283-GA-GAA
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000059.4(BRCA2):c.1813dupA(p.Ile605AsnfsTer11) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,601,314 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000059.4 frameshift
Scores
Clinical Significance
Conservation
Publications
- breast-ovarian cancer, familial, susceptibility to, 2Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
- Fanconi anemia complementation group D1Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
- pancreatic cancer, susceptibility to, 2Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- sarcomaInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- hereditary breast ovarian cancer syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Fanconi anemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- medulloblastomaInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Pathogenic. The variant received 16 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.1813dupA | p.Ile605AsnfsTer11 | frameshift_variant | Exon 10 of 27 | ENST00000380152.8 | NP_000050.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.1813dupA | p.Ile605AsnfsTer11 | frameshift_variant | Exon 10 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000530893.7 | c.1444dupA | p.Ile482AsnfsTer11 | frameshift_variant | Exon 10 of 27 | 1 | ENSP00000499438.2 | |||
| BRCA2 | ENST00000614259.2 | n.1813dupA | non_coding_transcript_exon_variant | Exon 9 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes 0.0000264 AC: 4AN: 151588Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000129 AC: 3AN: 232106 AF XY: 0.00000793 show subpopulations
GnomAD4 exome AF: 0.0000124 AC: 18AN: 1449726Hom.: 0 Cov.: 35 AF XY: 0.0000139 AC XY: 10AN XY: 720972 show subpopulations
Age Distribution
GnomAD4 genome 0.0000264 AC: 4AN: 151588Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2AN XY: 73980 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:18
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 allele predicted to encode a truncated non-functional protein.
PVS1, PM2, PS4
The c.1813dup (p.Ile605Asnfs*11) variant in the BRCA2 gene has been detected in multiple patients with breast and/or ovarian cancer [referred as 2034insA and 2041insA in PMID 9150150, 21324516, 22535016] and prostate cancer [PMID 21952622].This variant has been reported in four individuals from the ExAC database (http://exac.broadinstitute.org/variant/22-29091226-TA-T). This one bp duplication in exon 10 results in a frameshift and the creation of a premature stop codon. This variant is expected to result in a loss of function of the protein. It is thus classified as pathogenic.
Criteria applied: PVS1,PS4,PM5_STR,PM3
The c.1813dup (p.Ile605AsnfsTer11) change inserts one nucleotide within exon 10 of BRCA2 to cause a frameshift of the protein coding sequence and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of protein due to nonsense-mediated decay. This variant has been reported in individuals with breast and ovarian cancers (PMID: 9150150, 15024741, 21324516, 22729890, 29433453, 33471991), and was demonstrated to segregate with disease in a large family (PMID: 9150150). This variant has also been reported in patients with prostate and other cancers (PMID: 22729890, 21952622). In a case-control study, this variant was observed in 20 out of 60,466 breast cancer cases compared to just 1 out of 53,461 controls, resulting in an odds ratio of 17.6 (PMID: 33471991). This variant also has been detected in two compound heterozygous individuals with a second pathogenic BRCA2 mutation who exhibited clinical features consistent with Fanconi anemia (PMID: 15070707, 21548014). This variant has a maximum subpopulation frequency of 0.0066% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org), and it is absent in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (https://whi.color.com/). In summary, this variant meets criteria to be classified as pathogenic.
not provided Pathogenic:16
The BRCA2 c.1813dup (p.Ile605Asnfs*11) variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in affected individuals with breast and/or ovarian cancer (PMIDs: 9150150 (1997), 21324516 (2011), 22729890 (2012), 28324225 (2017), 30257646 (2018), and 36169650 (2022)). In a large scale breast cancer association study, it was found in individuals with breast cancer as well as a control (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). It has also been reported in individuals with prostate cancer (PMIDs: 29433453 (2018) and 32606146 (2020)). Based on the available information, this variant is classified as pathogenic.
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with hereditary breast and ovarian cancer (Frank 1998, Foretova 2004, Tai 2007, Kote-Jarai 2011, Becker 2012, Blay 2013, Pritzlaff 2017, Ibrahim 2018); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 21952622, 22535016, 9150150, 15024741, 18489799, 28324225, 30715675, 21324516, 23683081, 20104584, 25685387, 26834852, 22729890, 27225637, 27167707, 28008555, 22382806, 28873162, 28503720, 28664449, 28651617, 25085752, 23199084, 29433453, 21232165, 15689453, 9667259, 9585613, 25072261, 18042939, 28831036, 28724667, 29909963, 30720863, 28843361, 30014164, 30702160, 30322717, 30309722, 30257646, 21548014, 15070707, 28726808, 31454914, 26689913, 32318955, 31447099, 29176636, 32581362)
PM3_strong, PM5_strong, PVS1
The BRCA2 p.Ile605AsnfsX11 variant was identified in 8 of 22770 proband chromosomes (frequency: 0.00035) from individuals or families with Breast, Ovarian, or Prostate cancer (Becker, 2012; Heidemann, 2012; Janavicius, 2010; Kote-Jarai, 2011; Schubert, 1997; Zhang, 2011). The variant was shown to segregate in at least nine affected individuals with breast cancer (Schubert, 1997; Heidemann, 2012). The variant was also identified in dbSNP (ID: rs80359306) “With pathogenic allele”, HGMD, the BIC database (75X with class 5 clinical importance), and UMD (18X as a causal variant). The c.1813dupA duplication variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 605 and leads to a premature stop codon 11 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
This variant has been identified by standard clinical testing. Breast-ovarian cancer, familial, susceptibility to, 2
The BRCA2 c.1813dup; p.Ile605AsnfsTer11 variant (rs80359306), also known as 2041insA and 2034insA, is reported in the literature in several individuals with HBOC-related cancers (Becker 2012, Foretova 2004, Ibrahim 2018, Zhang 2011), and was demonstrated to segregate with disease in a large German family (Schubert 1997). This variant has also been reported in patients with prostate and other cancers (Ibrahim 2018, Kote-Jarai 2011). This variant is reported in ClinVar and is classified as pathogenic by an expert panel (Variation ID: 37762). This variant is only found on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by inserting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Functional data indicate that cell lines derived from patients harboring the c.1813dup variant are more susceptible than wild-type to radiation induced chromosomal abnormalities (Becker 2012). Based on available information, the p.Ile605AsnfsTer11 variant is considered to be pathogenic. REFERENCES Becker et al. A 24-color metaphase-based radiation assay discriminates heterozygous BRCA2 mutation carriers from controls by chromosomal radiosensitivity. Breast Cancer Res Treat. 2012; 135(1): 167-175. PMID: 22729890. Foretova et al. BRCA1 and BRCA2 mutations in women with familial or early-onset breast/ovarian cancer in the Czech Republic. Hum Mutat. 2004 Apr; 23(4): 397-398. PMID: 15024741. Ibrahim M et al. Male BRCA mutation carriers: clinical characteristics and cancer spectrum. BMC Cancer. 2018 Feb 13;18(1):179. PMID: 29433453. Kote-Jarai et al. BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients. Br J Cancer. 2011; 105(8): 1230-1234. PMID: 21952622. Schubert et al. BRCA2 in American families with four or more cases of breast or ovarian cancer: recurrent and novel mutations, variable expression, penetrance, and the possibility of families whose cancer is not attributable to BRCA1 or BRCA2. Am J Hum Genet. 1997; 60(5): 1031-1040. PMID: 9150150. Zhang et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011; 121(2): 353-357. PMID: 21324516.
DNA sequence analysis of the BRCA2 gene demonstrated a single base pair duplication in exon 10, c.1813dup. This sequence change results in an amino acid frameshift and creates a premature stop codon 11 amino acids downstream of the change, p.Ile605Asnfs*11. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated BRCA2 protein with potentially abnormal function. This sequence change has been described in the gnomAD database with a frequency of 0.001% in the overall population (dbSNP rs1253401667). This pathogenic sequence change has previously been described in several individuals with BRCA2-related cancers, including breast, ovarian, and prostate cancer (PMID: 9150150, 21324516, 21952622, 22535016, 22729890). These collective evidences indicate that this sequence change is pathogenic, however functional studies have not been performed to prove this conclusively.
BRCA2: PVS1, PS4, PM2
Hereditary breast ovarian cancer syndrome Pathogenic:7
Variant summary: The BRCA2 c.1813dupA (p.Ile605AsnfsX11) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 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 (e.g. c.1842dupT/ p.Asn615X, c.1889delC/ p.Thr630fsX14, etc). One in silico tool predicts a damaging outcome for this variant. This variant was found in 8/227550 control chromosomes at a frequency of 0.0000352, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). This variant has been reported in numerous affected individuals/families and has been classified this variant as pathogenic by multiple clinical diagnostic laboratories/reputable databases. Functional study showed variant with diminished DNA double strand break repair capacity (Becker_2012). Taken together, this variant is classified as pathogenic.
According to the ClinGen ENIGMA BRCA2 v1.1.0 criteria we chose these criteria: PVS1 (very strong pathogenic): see specifications table 4 exon 10: PVS1 and PM5_Stron (PTC), PS4 (strong pathogenic): Dorling 2021 (PMID: 33471991) 20/60,466 breast cancer cases & 1/53,461 controls & PS4 Calculator: OR = 17.69 (95%CI=2.37-131.85), PM3 (medium pathogenic): Wagner 2004 (PMID:15070707): found in trans with pathogenic variant c.7878G>C (p.Trp2626Cys) (Variation ID: 38125, Reviewed by expert panel) --> 2 P Myers 2011 (PMID: 21548014): found wih pathogenic variant c.631+2T>G (Variation ID: 9349, Reviewed by expert panel) --> 1 P ⇒ 3 P, PM5 (strong pathogenic): see specifications table 4 exon 10: PVS1 and PM5_Strong, PP4 (strong pathogenic): s. Combined LR Score = 104.582 (aus dem" ENIGMA BRCA1/BRCA2 specs 1.1.0"-Hub entnommen)
The p.Ile605fs variant in BRCA2 has been reported in >75 individuals with BRCA2- associated cancers (Breast Cancer Information Core (BIC) database), and segregat ed with disease in 7 affected relatives from 1 family (Schubert 1997). This vari ant has also been identified in 3/63362 European chromosomes by the Exome Aggreg ation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs80359306); howev er, this frequency is low enough to be consistent with the frequency of heredita ry breast and ovarian cancer (HBOC) in the general population. The p.Ile605fs va riant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 605 and leads to a premature termination codon 11 amino acids downstream. This alteration is then predicted to lead to a truncate d or absent protein. Heterozygous loss of function of the BRCA2 gene is an estab lished disease mechanism for HBOC. In summary, this variant meets our criteria t o be classified as pathogenic for HBOC in an autosomal dominant manner based upo n segregation studies, absence from controls, and predicted impact to protein.
This variant is a single nucleotide duplication in exon 10 of the BRCA2 mRNA c.(1813dupA). This creates a premature translational stop signal 11 amino acid residues later p.(Ile605Asnfs*11) and is expected to result in an absent or non-functional protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID:20104584). This genomic alteration is also reported as 2041insA, 2034insA, and c.1806_1807insA in the published literature. This variant is present in population databases (rs80359306). This duplication has been reported in international literature in individuals with breast, ovarian, and prostate cancer and in an individual with Fanconi anaemia (PMID:11179017, 14559878, 16683254, 10923033, 21324516, 22144684, 22729890, 26787237, 25479140, 28324225, 29433453, 30257646, 32606146, 36169650). The mutation database ClinVar contains entries for this variant where it is listed as pathogenic (VCV000037762.127). Based on the classification criteria set by the ACMG and AMP (PMID:25741868) this variant has been classified as pathogenic.
This sequence change creates a premature translational stop signal (p.Ile605Asnfs*11) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with breast, ovarian, and prostate cancer (PMID: 9150150, 21324516, 21952622, 22535016, 22729890). It has also been observed to segregate with disease in related individuals. This variant is also known as 1813insA, 2041insA, and 2034insA. ClinVar contains an entry for this variant (Variation ID: 37762). For these reasons, this variant has been classified as Pathogenic.
Hereditary cancer-predisposing syndrome Pathogenic:4
This variant inserts 1 nucleotide in exon 10 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 2034insA, 2040insA, 2041insA, 2041dupA, 2041_2042insA, c.1813insA and c.1806dupA in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in a breast cancer case-control meta-analysis in 20 cases and 1 unaffected control, which is estimated to have an odds ratio for pathogenicity of OR=17.689 (95%CI 2.374 to 131.809; p-value<0.001) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001802) and has also been reported in individuals affected with breast, ovarian, pancreatic, prostate and neuroendocrine cancers (PMID: 9150150, 9667259, 18042939, 20104584, 21324516, 21952622, 22729890, 25072261, 28724667, 29433453) and suspected hereditary breast and ovarian cancer families (PMID: 11802209, 21232165, 24156927). In one family, this variant was reported in 11 women affected with breast cancer across three generations (PMID: 9150150). This variant also has been detected in two compound heterozygous individuals with a second pathogenic BRCA2 mutation who exhibited clinical features consistent with Fanconi anemia (PMID: 15070707, 21548014). Haplotype analysis suggests that this variant may be a founder mutation and is common in people of German ancestry (PMID: 9585613, 23199084). This variant has been identified in 3/232106 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.
The c.1813dupA (p.I605Nfs*11) alteration, located in coding exon 9 of the BRCA2 gene, consists of a duplication of A at position 1813, causing a translational frameshift with a predicted alternate stop codon after 11 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, the AA allele has an overall frequency of 0.001% (3/232106) total alleles studied. The highest observed frequency was 0.007% (1/15242) of African alleles. This mutation has been detected in multiple individuals with breast, ovarian and prostate cancer from HBOC kindreds (Foretova, 2004; Janaviius, 2010; Zhang, 2011; Kote-Jarai, 2011; Carter, 2018; Ibrahim, 2018; Deng, 2019; Mehemmai, 2020). In one study, this variant was reported in 20/60,466 breast cancer cases and in 1/53,461 controls (Dorling, 2021). This alteration, in compound heterozygosity with another BRCA2 mutation, was also reported in an individual with Fanconi anemia (Myers, 2012). The c.1813dupA pathogenic mutation was reported in two unrelated probands with a personal and/or family history of breast/ovarian cancers and was shown to diminish DNA double strand break repair capacity in response to irradiation (Becker , 2012). Of note, this mutation is also referred to as 2041insA, 2034insA,and c.1806_1807insA in some of the published literature. Based on the available evidence, this alteration is classified as pathogenic.
Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.
Familial cancer of breast Pathogenic:3
Criteria applied: PVS1,PS4,PM5_STR
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:2
Criteria applied: PVS1,PS4,PM5_STR
Breast and/or ovarian cancer Pathogenic:2
BRCA2-related disorder Pathogenic:1Other:1
Variant interpreted as Pathogenic and reported on 09-10-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
The BRCA2 c.1813dupA variant is predicted to result in a frameshift and premature protein termination (p.Ile605Asnfs*11). This variant (alternatively described as 1813insA and 2041dupA) has been documented multiple times in individuals with personal and/or family history of breast/ovarian cancers (Son et al. 2012. PubMed ID: 22382806; Meisel et al. 2017. PubMed ID: 28324225), and prostate cancer (Kote-Jarai et al. 2011. PubMed ID: 21952622). A functional in vitro study using blood lymphocytes on this variant has demonstrated significantly higher radiation-induced chromosomal aberrations (Becker et al. 2012. PubMed ID: 22729890). This variant is reported in 0.0066% of alleles in individuals of African descent in gnomAD and is classified as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/37762/). Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic.
Carcinoma of pancreas Pathogenic:1
BRCA2-related cancer predisposition Pathogenic:1
This variant inserts 1 nucleotide in exon 10 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 2034insA, 2040insA, 2041insA, 2041dupA, 2041_2042insA, c.1813insA and c.1806dupA in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in a breast cancer case-control meta-analysis in 20 cases and 1 unaffected control, which is estimated to have an odds ratio for pathogenicity of OR=17.689 (95%CI 2.374 to 131.809; p-value<0.001) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001802) and also has been reported in individuals affected with breast, ovarian, pancreatic, prostate and neuroendocrine cancers (PMID: 9150150, 9667259, 18042939, 20104584, 21324516, 21952622, 22729890, 25072261, 28724667, 29433453) and suspected hereditary breast and ovarian cancer families (PMID: 11802209, 21232165, 24156927). In one family, this variant was reported in 11 women affected with breast cancer across three generations (PMID: 9150150). This variant also has been detected in two compound heterozygous individuals with a second pathogenic BRCA2 mutation who exhibited clinical features consistent with Fanconi anemia (PMID: 15070707, 21548014). Haplotype analysis suggests that this variant may be a founder mutation and is common in people of German ancestry (PMID: 9585613, 23199084). This variant has been identified in 3/232106 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.
Breast carcinoma Pathogenic:1
Medulloblastoma;C0346153:Familial cancer of breast;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C2931456:Familial prostate cancer;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Pathogenic:1
Hereditary breast ovarian cancer syndrome;C1838457:Fanconi anemia complementation group D1 Other:1
Variant classified as Pathogenic and reported on 05-11-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at