NM_000059.4:c.8537_8538delAG
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000059.4(BRCA2):c.8537_8538delAG(p.Glu2846GlyfsTer22) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000684 in 1,461,838 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.8537_8538delAG | p.Glu2846GlyfsTer22 | frameshift_variant | Exon 20 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000530893.7 | c.8168_8169delAG | p.Glu2723GlyfsTer22 | frameshift_variant | Exon 20 of 27 | 1 | ENSP00000499438.2 | |||
| BRCA2 | ENST00000614259.2 | n.*595_*596delAG | non_coding_transcript_exon_variant | Exon 19 of 26 | 2 | ENSP00000506251.1 | ||||
| BRCA2 | ENST00000614259 | n.*595_*596delAG | 3_prime_UTR_variant | Exon 19 of 25 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251142Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135704
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461838Hom.: 0 AF XY: 0.00000825 AC XY: 6AN XY: 727220
GnomAD4 genome
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:7
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Variant allele predicted to encode a truncated non-functional protein. -
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not provided Pathogenic:6
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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; Not observed at a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 8765delAG and 8765_8766delAG; This variant is associated with the following publications: (PMID: 23929434, 8673090, 16168118, 18489799, 21947752, 23302520, 23621881, 10422801, 15024741, 20694749, 26295337, 30014164, 28918466, 29086229, 29506128, 23199084, 25884701, 19656164, 26656232, 17640379, 25452441, 22798144, 21348412, 27836010, 27603373, 27160020, 25085752, 19619314, 15382066, 11512557, 9792861, 9634522, 21324516, 17591843, 16047344, 29560538, 22401979, 30720243, 30322717, 29625052) -
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This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals affected with breast cancer, ovarian cancer, and pancreatic cancer in the published literature (PMID: 30322717 (2018), 29625052 (2018), 29506128 (2018), 29086229 (2018), 21324516 (2011)). Based on the available information, this variant is classified as pathogenic. -
PM5_strong, PVS1 -
Hereditary breast ovarian cancer syndrome Pathogenic:5
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The p.Glu2846fs variant in BRCA2 is a well-established pathogenic founder varian t for several populations, including French Canadians, Jewish-Yemenites, and Nor thern Sardinian (Tonin 1998, Lerer 1998, Ferla 2007). This variant has been ide ntified in 1/66688 European chromosomes by the Exome Aggregation Consortium (ExA C, http://exac.broadinstitute.org; dbSNP rs80359716). This frequency is low enou gh 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 2846 and leads to a premature termination codon 22 amino acids downstream. This alteratio n is then predicted to lead to a truncated or absent protein. Heterozygous loss of BRCA2 function is an established disease mechanism in HBOC. In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an autosom al dominant manner. -
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Variant summary: BRCA2 c.8537_8538delAG (p.Glu2846GlyfsX22) 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 1.2e-05 in 251142 control chromosomes. c.8537_8538delAG has been reported in the literature in many individuals and families affected with Hereditary Breast And Ovarian Cancer Syndrome (example Phelan_1996, Machackova_2008, Ghadirian_2014) including 76 patients from the BIC database. It is commonly reported as a pathogenic variant in French Canadian, Yemenite Jewish, and Northern Sardinian populations (example Lerer_1998, Manning_2001, Palomba_ 2007). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories and reputable databases have classified this variant as pathogenic in ClinVar. Based on the evidence outlined above, the variant was classified as pathogenic. -
This sequence change creates a premature translational stop signal (p.Glu2846Glyfs*22) 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 present in population databases (rs80359714, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 8673090, 21324516, 22401979). It is commonly reported in individuals of French Canadian, Yemenite Jewish, and Northern Sardinian ancestry (PMID: 9634522, 9792861, 11512557, 15382066, 17640379, 19619314, 27603373). This variant is also known as 8765delAG. For these reasons, this variant has been classified as Pathogenic. -
Breast and/or ovarian cancer Pathogenic:3
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Hereditary cancer-predisposing syndrome Pathogenic:2
The c.8537_8538delAG pathogenic mutation, located in coding exon 19 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 8537 to 8538, causing a translational frameshift with a predicted alternate stop codon (p.E2846Gfs*22). This mutation has been reported in multiple individuals and families with hereditary breast and ovarian cancer (HBOC) syndrome (Foretova L et al. Hum. Mutat. 2004 Apr;23(4):397-8; Palomba G et al. Cancer, 2005 Sep;104:1172-9; Machackova E et al. BMC Cancer, 2008 May;8:140; Zhang S et al. Gynecol. Oncol. 2011 May;121(2):353-7; Abd-Rabbo D et al. Cancer Prev. Res. 2012 May;5(5):765-77; Belanger MH et al. J Ovarian Res, 2015 Mar;8:1; El Ghorayeb N et al. Medicine (Baltimore), 2016 Sep;95:e4756; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Bernstein-Molho R et al. Breast Cancer Res Treat, 2018 02;167:697-702; Felix GES et al. Fam Cancer, 2018 10;17:471-483; Lowery MA et al. J Natl Cancer Inst, 2018 10;110:1067-1074; De Talhouet S et al. Sci Rep, 2020 04;10:7073; Dorling et al. N Engl J Med. 2021 02;384:428-439), and has also been reported in a family with a history of male breast and prostate cancer (Phelan CM et al. Nat. Genet. 1996 May;13(1):120-2). This mutation has also been reported in patients with pancreatic and gastric cancers (Halpern N et al. Onco Targets Ther, 2020 Nov;13:11637-11644; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This alteration is known to be one of the more commonly occurring BRCA2 mutations in several different regions in Europe and North America (Tonin PN et al. Am J Hum Genet, 1998 Nov;63:1341-51; Manning AP et al. Hum Hered, 2001;52:116-20; Palomba G et al. BMC Cancer, 2007 Jul;7:132; Janavicius R. EPMA J. 2010 Sep;1(3):397-412). Of note, this alteration is also designated as 8535delAG, 8765delAG, c.8764_8765delAG and c.8537_8538del2 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. -
This variant deletes 2 nucleotides in exon 20 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 8765delAG in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported as a recurrent mutation in individuals and families affected with breast and ovarian cancer in North American, Europe and the Middle East (PMID: 8673090, 9634522, 15024741, 15382066, 16047344, 29446198, 33471991). A multifactorial analysis has reported a likelihood ratio for pathogenicity greater than 40,000:1 based on health history of 24 probands (PMID: 31853058). Haplotype analyses suggest that this mutation may have arisen independently as founder mutations in the French-Canadian, Yemenite Jewish and Sardinian populations (PMID: 11512557, 17640379). This variant has been identified in 3/251142 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. -
BRCA2-related cancer predisposition Pathogenic:1
This variant deletes 2 nucleotides in exon 20 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported as a recurring pathogenic variant in French Canadian, Sardinian, and Yemenite Jewish populations (PMID: 9792861, 17640379, 23621881, 29086229). This variant has been identified in 3/251142 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. -
Malignant tumor of breast Pathogenic:1
The BRCA2 p.Glu2846GlyfsX22 variant was identified in 21 of 4958 proband chromosomes (frequency: 0.004) from individuals or families with breast and ovarian cancer (Phelan 1996, Zhang 2011, Machackova 2008, Pruss 2014, Seong M-W 2009, Tung 2016). The variant was also identified in the following databases: dbSNP (ID: rs80359714) as “With Pathogenic allele”, Clinvitae database (classified as pathogenic by ClinVar and Invitae), ARUP Laboratories BRCA Mutations Database (classification), the ClinVar database (classified as pathogenic by Invitae, Ambry genetics, GeneDx, LMMPHPM, QDNISJC, COGR, Pathway Genomics, BIC,OMIM, SCRP), COGR database (classified as pathogenic by a clinical laboratories MESHWCRI, LMM, CHEO, QUEENSU, NYG), the BIC database (76X with clinical importance), and UMD (16X with a causal classification). The variant was also identified in Exome Aggregation Consortium database (August 8, 2016) in the European population in 1 of 121324 chromosomes (freq. 0.000008). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The c.8537_8538del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 2846 and leads to a premature stop codon 22 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. -
Familial cancer of breast Pathogenic:1
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Familial cancer of breast;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at