rs80359702
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.8247_8248del(p.Lys2750AspfsTer13) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000137 in 1,461,858 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. Q2749Q) 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 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.8247_8248del | p.Lys2750AspfsTer13 | frameshift_variant | 18/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.8247_8248del | p.Lys2750AspfsTer13 | frameshift_variant | 18/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461858Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727232
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:4
Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Mar 30, 2011 | - - |
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 | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
Pathogenic, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Apr 22, 2016 | Variant allele predicted to encode a truncated non-functional protein. - |
Hereditary breast ovarian cancer syndrome Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | This sequence change creates a premature translational stop signal (p.Lys2750Aspfs*13) 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/ovarian cancer (PMID: 15340362, 22762150). This variant is also known as 8475delGA. ClinVar contains an entry for this variant (Variation ID: 52536). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 24, 2022 | Variant summary: BRCA2 c.8247_8248delGA (p.Lys2750AspfsX13) 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 was absent in 249060 control chromosomes. c.8247_8248delGA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Five clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified 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 | research | Genetics Program, Instituto Nacional de Cancer | Nov 01, 2021 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 01, 2020 | This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals and families with breast cancer in the published literature (PMID: 22762150 (2012) and 15340362 (2004)). Based on the available information, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 15, 2021 | 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (Lek 2016); Reported in individuals with personal or family history of BRCA2-related cancers (Marroni 2004, Lecarpentier 2012, Maxwell 2016, Rizzolo 2019, Toss 2019, Darst 2021); Also known as c.8246_8247delAG or 8475_8476delGA; This variant is associated with the following publications: (PMID: 15340362, 22762150, 30787465, 27153395, 30736435, 30613976, 32853339) - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 25, 2022 | The c.8247_8248delGA pathogenic mutation, located in coding exon 17 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 8247 to 8248, causing a translational frameshift with a predicted alternate stop codon (p.K2750Dfs*13). This alteration has been identified in multiple high-risk breast/ovarian cancer families (Marroni, F et al. Eur J Hum Genet. 2004 Nov;12(11):899-906; Musolino, A et al. Breast. 2007 Jun;16(3):280-92; Maxwell KN et al. Am. J. Hum. Genet. 2016 May;98:801-817). This variant has also been report in 2/81 male breast cancer patients who had multi-gene panel testing (Scarpitta R et al. Breast Cancer Res Treat, 2019 Dec;178:557-564). Of note, this mutation is also designated as 8475delGA. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 | Nov 07, 2022 | This variant deletes 2 nucleotides in exon 18 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 at least 5 individuals affected with breast and/or ovarian cancer, including 1 male individual and 1 individual affected with both breast and ovarian cancer, (PMID: 11879560, 17257844, 22776961, 27163896, 34072659) and has been identified in 36 families among the CIMBA participants (PMID: 29446198). 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. - |
Breast and/or ovarian cancer Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 09, 2022 | - - |
Familial cancer of breast Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 22, 2023 | - - |
Diffuse midline glioma, H3 K27-altered Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital | May 31, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at