rs397507922
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_000059.4(BRCA2):c.7617+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Consequence
NM_000059.4 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.7617+1G>A | splice_donor_variant | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.7617+1G>A | splice_donor_variant | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461518Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727074
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:5
Pathogenic, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Apr 15, 2016 | Allele-specific assay on patient-derived mRNA demonstrated that the variant allele produces only predicted non-functional transcripts. Variant allele produces r.7436_7617del transcript (encoding predicted non-functional protein). - |
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 | BRCAlab, Lund University | Mar 02, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Department of Medical Genetics, Oslo University Hospital | Jan 20, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Dec 29, 2011 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change affects a donor splice site in intron 15 of the BRCA2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer (PMID: 21184276, 24123850). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 52362). Studies have shown that disruption of this splice site results in skipping of exon 15 and introduces a premature termination codon (PMID: 18712473, 21184276, 24123850). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 21, 2018 | This variant is denoted BRCA2 c.7617+1G>A or IVS15+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 15 of the BRCA2 gene. Using alternate nomenclature, this variant would be defined as BRCA2 7845+1G>A or 7829+1G>A. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing and several assays have identified that this variant results in abnormal splicing leading to skipping of exon 15 and a truncated protein (Bergthorsson 2001, Thomassen 2011, de Garibar 2014). This variant has been reported in association with breast and ovarian cancer and is a frequently observed variant in Danish and Spanish individuals (Bergthorsson 2001, Gutierrez-Enriquez 2009, Thomassen 2011, Zhang 2011, de Juan Jimenez 2013, de Garibay 2014, Roed Nielsen 2016). We consider this variant to be pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Feb 06, 2024 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 04, 2023 | This variant causes a G to A nucleotide substitution at the +1 position of intron 15 of the BRCA2 gene. RNA studies have shown that this variant causes skipping of exon 15, resulting in premature truncation (PMID: 11389159, 21184276, 24123850, 31191615). This variant has been reported in individuals affected with breast/ovarian cancer (PMID: 11389159, 20927582, 21184276, 24123850, 26187060, 26360800, 26833046) or pancreatic cancer (PMID: 12097290, 17301269). 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 29, 2022 | The c.7617+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 14 of the BRCA2 gene. This nucleotide position is highly conserved in available vertebrate species. This alteration has been described as a Danish founder pathogenic mutation and it segregates strongly with disease in many Danish families (Thomassen M et al. Breast Cancer Res. Treat., 2011 Jul;128:179-85; de Juan Jiménez I et al. Fam. Cancer, 2013 Dec;12:767-77; Roed Nielsen H et al. Acta Oncol, 2016 Sep;55:38-44; Nielsen HR et al. Fam. Cancer, 2016 Oct;15:507-12 ). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA analyses using patient RNA and minigene assays have shown this alteration results in complete loss of exon 15 (Ambry internal data; Bergthorsson JT et al. J. Med. Genet., 2001 Jun;38:361-8; Gutiérrez-Enríquez S et al. Breast Cancer Res. Treat., 2009 Sep;117:461-5; Thomassen M et al. Breast Cancer Res. Treat., 2011 Jul;128:179-85; Fraile-Bethencourt E et al. Front Genet, 2019 May;10:503; de Garibay GR et al. Hum Mutat, 2014 Jan;35:53-7). Of note, this alteration is also designated as IVS15+1G>A and 7845+1G>A in published literature. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. - |
Familial cancer of breast Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 01, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at