13-32336936-C-CA
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000059.4(BRCA2):c.2588dup(p.Asn863LysfsTer18) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000503 in 1,590,738 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. Q861Q) has been classified as Likely benign. 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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.2588dup | p.Asn863LysfsTer18 | frameshift_variant | 11/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.2588dup | p.Asn863LysfsTer18 | frameshift_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151990Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000880 AC: 2AN: 227148Hom.: 0 AF XY: 0.0000163 AC XY: 2AN XY: 122978
GnomAD4 exome AF: 0.00000487 AC: 7AN: 1438748Hom.: 0 Cov.: 33 AF XY: 0.00000560 AC XY: 4AN XY: 714834
GnomAD4 genome AF: 0.00000658 AC: 1AN: 151990Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74238
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:7
Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | May 01, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 10, 2023 | The c.2588dup (p.Asn863Lysfs*18) variant in the BRCA2 gene is located on the exon 11 and is predicted to cause shift of reading frame that introduces a premature translation termination codon (p.Asn863Lysfs*18), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with breast and/or ovarian cancer (PMID: 25863477, 20694749, 21324516, 12942367, 9792861). Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 8988179, 11897832, 29446198). The variant is reported in ClinVar as pathogenic (ID: 37793) and reviewed by the expert panel. The variant is rare in general population according to gnomAD (2/227148). Therefore, the c.2588dup (p.Asn863Lysfs*18) variant of BRCA2 has been classified as pathogenic. - |
Pathogenic, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Sep 08, 2016 | Variant allele predicted to encode a truncated non-functional protein. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 07, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The p.Asn862LysfsX18 duplication variant has been previously reported in the literature in 2 of 2740 chromosomes from individuals with hereditary breast and or ovarian cancer (pancreatic cancer was also suspected in one family) (Gao 2000, Zhang 2011). The variant is also reported in the UMD (3x as causal) and BIC (11x as clinically important) databases. In addition, it was reported in 3/4403 chromosomes from the exome variant server database and in dbSNP (ID#:rs80359335) in individuals of African American ancestry, increasing the likelihood this variant may be present at low frequency in this population. The p.Asn862LysfsX18 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 862 and leads to a premature stop codon 18 amino acids downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants are an established mechanism of hereditary breast and ovarian cancer for the BRCA2 gene. In summary, based on the above information, this variant is classified as pathogenic. - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 24, 2023 | 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 multiple individuals with a personal and/or family history of BRCA2-related cancers (Tonin et al., 1998; Kanaan et al., 2003; Cavallone et al., 2010; Song et al., 2014; Rebbeck et al., 2018) and in an individual with Fanconi anemia (Wagner et al., 2004); 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 2816dupA and 2816insA; This variant is associated with the following publications: (PMID: 25863477, 29922827, 28888541, 11030417, 21324516, 9792861, 15382066, 16905680, 25884701, 10422801, 24728189, 15645491, 17851763, 24301060, 15070707, 15131399, 12942367, 9667259, 20694749, 17148771, 15004464, 16847550, 25428789, 30130155, 29446198, 30702160, 31825140, 30787465, 33471991) - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 13, 2018 | The variant results in a shift of the reading frame, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity. - |
Hereditary breast ovarian cancer syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 21, 2019 | Variant summary: BRCA2 c.2588dupA (p.Asn863LysfsX18) 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. The variant was absent in 222684 control chromosomes (gnomAD). c.2588dupA has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Gao_2000, Frank_1998, Euhus_2002, Kanaan_2003, Risch_2006, Zheng_2018). These data indicate that the variant is very likely to be associated with disease. Eight ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 20, 2023 | This sequence change creates a premature translational stop signal (p.Asn863Lysfs*18) 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 cancer, ovarian cancer, and Fanconi anemia (PMID: 11030417, 15070707, 21324516, 24728189). This variant is also known as 2816insA. ClinVar contains an entry for this variant (Variation ID: 37793). For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 17, 2021 | The c.2588dupA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of A at nucleotide position 2588, causing a translational frameshift with a predicted alternate stop codon (p.N863Kfs*18). This mutation has been identified in multiple individuals with personal and/or family histories of breast, ovarian, and pancreatic cancers (Gao Q et al. Hum. Genet. 2000 Aug;107:186-91; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Song H et al. Hum. Mol. Genet. 2014 Sep;23:4703-9; Park JS et al. Clin Breast Cancer, 2018 10;18:362-373.e1; Dorling et al. N Engl J Med. 2021 02;384:428-439). Reports of this alteration in individuals of French Canadian ancestry suggest a founder effect in this population (Tonin PN et al. Am. J. Hum. Genet. 1998 Nov;63:1341-51; Cavallone L et al. Fam. Cancer 2010 Dec;9:507-17). This mutation was identified in a 5-year old boy with Fanconi Anemia, with a second unidentified splicing alteration suspected based on cDNA analysis (Wagner JE et al. Blood 2004 Apr;103:3226-9). Of note, this alteration is also designated as 2816insA 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 12, 2022 | This variant inserts 1 nucleotide 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 cancer (PMID: 16760289, 25428789, 30130155) and ovarian cancer (PMID: 21324516, 24728189). This variant has been identified in 2/227148 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 and/or ovarian cancer Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Dec 04, 2015 | - - |
Familial cancer of breast Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 19, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at