13-32379885-CAAAA-CAAAAA
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000059.4(BRCA2):c.9097dupA(p.Thr3033AsnfsTer11) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,612,818 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
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.9097dupA | p.Thr3033AsnfsTer11 | frameshift_variant | Exon 23 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000530893.7 | c.8728dupA | p.Thr2910AsnfsTer11 | frameshift_variant | Exon 23 of 27 | 1 | ENSP00000499438.2 | |||
| BRCA2 | ENST00000614259.2 | n.*1155dupA | non_coding_transcript_exon_variant | Exon 22 of 26 | 2 | ENSP00000506251.1 | ||||
| BRCA2 | ENST00000614259 | n.*1155dupA | 3_prime_UTR_variant | Exon 22 of 25 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes 0.00000659 AC: 1AN: 151796Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461022Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 726774
GnomAD4 genome 0.00000659 AC: 1AN: 151796Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74146
ClinVar
Submissions by phenotype
not provided Pathogenic:11
The BRCA2 c.9097dup (p.Thr3033Asnfs*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 individuals with breast cancer (PMID: 33558524 (2021), 32959997 (2020), 32846166 (2020), 22970155 (2012), ovarian cancer (PMID: 28541631 (2017)), and pancreatic cancer (PMID: 259407172015)). The variant has also been reported in a child with Fanconi Anemia (PMID: 21138478 (2011)). The frequency of this variant in the general population, 0.000012 (3/245952 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -
PVS1, PP4, PM2_SUP -
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The BRCA2 c.9097dupA; p.Thr3033AsnfsTer11 variant (rs397507419) has been reported in multiple individuals with breast or ovarian cancer (Kim 2012, Kwong 2012, Machackova 2008, Serova-Sinilnikova 1997, Zhao 2017). It is reported as pathogenic in ClinVar (Variation ID: 38208), and is only observed on 3 alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant introduces a frameshift by duplicating a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered pathogenic. References: Kim H et al. Characteristics and spectrum of BRCA1 and BRCA2 mutations in 3,922 Korean patients with breast and ovarian cancer. Breast Cancer Res Treat. 2012; 134(3):1315-26. Kwong A et al. Identification of BRCA1/2 founder mutations in Southern Chinese breast cancer patients using gene sequencing and high resolution DNA melting analysis. PLoS One. 2012; 7(9):e43994. Machackova E et al. Spectrum and characterisation of BRCA1 and BRCA2 deleterious mutations in high-risk Czech patients with breast and/or ovarian cancer. BMC Cancer. 2008; 8:140. Serova-SInilnikova O et al. BRCA2 mutations in hereditary breast and ovarian cancer in France. Am J Hum Genet. 1997; 60(5):1236-9. Zhao Q et al. Germline and somatic mutations in homologous recombination genes among Chinese ovarian cancer patients detected using next-generation sequencing. -
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PVS1, PS4, PM2 -
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 a personal or family history consistent with pathogenic variants in this gene (PMID: 9150172, 12161607, 22798144, 25940717, 23569316, 29335925, 35264596); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 9325dupA, 9317insA, or 9089_9090insA; This variant is associated with the following publications: (PMID: 12161607, 26852015, 26843898, 35534704, 32073954, 36555431, 34284872, 36637704, 36243179, 36721989, 34196900, 35864222, 28324225, 27882536, 32772980, 32599251, 32875559, 29922827, 9150172, 22970155, 21138478, 21913181, 23569316, 22798144, 18489799, 23242139, 25940717, 27157322, 27393621, 20383589, 25330149, 29752822, 29907814, 28692638, 28541631, 29335925, 28993434, 29310832, 30720863, 30287823, 30720243, 30702160, 30093976, 31159747, 31396961, 30736435, 31957001, 32072338, 32029870, 31214711, 32846166, 31589614, 31825140, 33558524, 32338768, 30875412, 30613976, 31742824, 32959997, 31360904, 31723001, 35418818, 33804961, 29360550, 31209999, 28724667, 35264596) -
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:9
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Variant allele predicted to encode a truncated non-functional protein. -
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Hereditary breast ovarian cancer syndrome Pathogenic:5
This sequence change creates a premature translational stop signal (p.Thr3033Asnfs*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 and ovarian cancer, pancreatic cancer, and Fanconi anemia (PMID: 9150172, 21138478, 22970155, 25940717). This variant is also known as c.9097_9098insA, 9325insA and 9317insA. ClinVar contains an entry for this variant (Variation ID: 38208). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). For these reasons, this variant has been classified as Pathogenic. -
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The p.Thr3033AsnfsX11 variant in BRCA2 has been reported in >20 individuals with BRCA2-associated cancers (Serova-Sinilnikova 1997, Kopic 2011, Kwong 2012, Holter 2015, Wong-Brown 2015, Breast Cancer Information Core (BIC) database). This variant has been identified in 1/15908 African chromosomes by the Genome Aggregation Database (GnomAD, http://gnomad.broadinstitute.org); however, 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 3033 and leads to a premature termination codon 11 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 in hereditary breast and ovarian cancer (HBOC). In addition, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282467.1). In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1, PS4, PM2. -
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Familial cancer of breast Pathogenic:4
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This sequence change duplicates one base in exon 23 of BRCA2 mRNA (c.9097dupA), causing a frameshift after codon 3033 and the creation of a premature translation stop signal 11 amino acid residues later p.(Thr3033Asnfs*11). This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA2 are known to be pathogenic. This variant is also known as c.9097_9098insA, 9325insA and 9317insA in the literature and has been reported in individuals affected with breast and ovarian cancer, pancreatic cancer, and Fanconi anemia (PMID: 22970155 , PMID: 9150172 PMID: 25940717 , PMID: 21138478). The mutation database ClinVar contains entries for this variant (Variation ID: 38208). -
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ACMG Guidelines 2015 criteria The BRCA2 variant p.Thr3033Asnfs is a known pathogenic variant in exon 23 in the Nucleic acid-binding OB-fold (T2968-3184L aa) domain, which binds to single-stranded nucleic acids (staphylococcal nuclease and aspartyl-tRNA synthetase) or oligosaccharides (B subunits of enterotoxin and verotoxin-1), and has been termed the oligonucleotide/oligosaccharide binding motif, or OB fold (PMID: 12769718). This frameshift mutation disrupts the function of the domain which is an established disease mechanism in hereditary breast and ovarian cancer (PVS1 Pathogenic Very Strong). This mutation hotspot has 31 pathogenic variants (PM1 Pathogenic Moderate). This variant is not found in GnomAD exomes neither in GnomAD genomes (PM2 Pathogenic Moderate). 1 pathogenic prediction from GERP versus no benign predictions supports its deleterious effect (PP3 Pathogenic Supporting). The variant has been classified as pathogenic by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282467.1) (PP5 Pathogenic Supporting). The variant p.Thr3033Asnfs was found in a 48-year-old female with unilateral breast cancer and a strong family history. -
Breast and/or ovarian cancer Pathogenic:3
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Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:2
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Criteria applied: PVS1,PM5_STR -
Hereditary cancer-predisposing syndrome Pathogenic:2
This variant inserts 1 nucleotide in exon 23 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 9325insA, 9317insA and c.9090insA in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over ten individuals and families affected with breast and ovarian cancer (PMID: 9150172, 18489799, 22798144, 22970155, 24010542, 24916970, 25682074, 28541631, 28692638, 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA2_001002) and additional individuals affected with pancreatic, prostate and biliary tract cancer (PMID: 25940717, 29360550, 31214711). This variant has been described as a recurrent mutation in hereditary breast and ovarian cancer families in the Chinese population (PMID: 22970155). This variant has also been reported in the compound heterozygous state in an individual affected with Fanconi anaemia (PMID: 21138478). This variant has not been identified 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.9097dupA pathogenic mutation, located in coding exon 22 of the BRCA2 gene, results from a duplication of one nucleotide at position 9097, causing a translational frameshift with a predicted alternate stop codon (p.T3033Nfs*11). This mutation has been described in multiple breast, ovarian and/or pancreatic cancer families across multiple ethnic groups (Serova-Sinilnikova OM et al. Am. J. Hum. Genet. 1997 May;60:1236-9; Machackova E et al. BMC Cancer. 2008 May;8:140; Kwong A et al. PLoS ONE. 2012 Sep;7:e43994; Konstantopoulou I et al. Clin. Genet. 2014 Jan;85:36-42; Holter S et al. J. Clin. Oncol. 2015 Oct;33:3124-9; Kwong A et al. J. Mol. Diagn. 2016 Jul;18(4):580-94; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295(5):1227-1238; Zhao Q et al. J. Gynecol. Oncol. 2017 Jul;28(4):e39; Rebbeck TR et al. Hum Mutat. 2018 May;39(5):593-620). This mutation has also been reported in male patients with breast cancer and in a male patient with biliary tract cancer (Fostira F et al. Breast Cancer Res Treat. 2018 May;169(1):105-113; Wardell CP et al. J Hepatol. 2018 May;68(5):959-969; Momozawa Y et al. Nat Commun. 2018 Oct 4;9(1):4083). This mutation, in compound heterozygosity with another BRCA2 mutation, was also detected in a child with clinical features of Fanconi anemia (Kopic S et al. Acta Paediatr. 2011 May;100:780-3). Of note, this alteration is also designated as 9325insA and 9325dupA in published literature. 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. -
BRCA2-related cancer predisposition Pathogenic:1
This variant inserts 1 nucleotide in exon 23 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 9325insA, 9317insA and c.9090insA in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over ten individuals and families affected with breast and ovarian cancer (PMID: 9150172, 18489799, 22798144, 22970155, 24010542, 24916970, 25682074, 28541631, 28692638, 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA2_001002) and additional individuals affected with pancreatic, prostate and biliary tract cancer (PMID: 25940717, 29360550, 31214711). This variant has been described as a recurrent mutation in hereditary breast and ovarian cancer families in the Chinese population (PMID: 22970155). This variant has also been reported in the compound heterozygous state in an individual affected with Fanconi anaemia (PMID: 21138478). This variant has not been identified 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. -
Malignant lymphoma, large B-cell, diffuse Pathogenic:1
Post-initial therapy specimen. -
Gastric cancer Pathogenic:1
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Familial cancer of breast;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:1
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Ovarian neoplasm Pathogenic:1
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Breast carcinoma Pathogenic:1
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See cases Pathogenic:1
ACMG criteria used to clasify this variant:PVS1, PS4_MOD, PM2_SUP -
Malignant tumor of breast Pathogenic:1
The BRCA2 p.Thr3033Asnfs*11 variant was identified in 9 of 10056 proband chromosomes (frequency: 0.0009) from Australian, Polish, French, Czech, Chinese, Greek and Korean individuals or families with triple negative breast cancer, (high risk) breast or ovarian cancer, HBOC, or pancreatic cancer (Wong 2015, Serova-Sinilnicova 1997, Machackova 2008, Kwong 2012, Konstantopoulou 2014, Kang 2015, Holter 2015). The variant was also identified in a 4 year old with Fanconi anemia with a hepatoblastoma (Kopic 2010). The variant was identified in dbSNP (ID: rs754205122) as “With Pathogenic allele”, in ClinVar (as pathogenic, reviewed by an expert panel 2016 with 15 submitters), Clinvitae (7x), COGR (2x clinical laboratories), Cosmic (1x in a colon adenocarcinoma), LOVD 3.0 (1x), UMD-LSDB (19x as Causal, and as co-occurring with a pathogenic BRCA1 variant: c.3756_3759delGTCT, p.Ser1253ArgfsX10), BIC Database (27x with clinical importance classified pathogenic), and ARUP Laboratories (classified as definitely pathogenic). The variant was not identified in MutDB, or Zhejiang University database. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.9097dup variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 3033 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at