rs730881616
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PM4_Supporting
The NM_000059.4(BRCA2):c.8588_8590dup(p.Glu2863dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L2862L) has been classified as Likely benign.
Frequency
Consequence
NM_000059.4 inframe_insertion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.8588_8590dup | p.Glu2863dup | inframe_insertion | 20/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.8588_8590dup | p.Glu2863dup | inframe_insertion | 20/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461832Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727214
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 04, 2019 | Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek 2016); Also known as 8816_8818dupAAG - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 30, 2019 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 05, 2022 | This variant causes the duplication of glutamic acid 2863 in the BRCA2 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 03, 2023 | The c.8588_8590dupAAG variant (also known as p.E2863dup), located in coding exon 19 of the BRCA2 gene, results from an in-frame duplication of AAG at nucleotide positions 8588 to 8590. This results in the duplication of an extra residue between codons 2863 and 2864. The in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Hereditary breast ovarian cancer syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | This variant, c.8588_8590dup, results in the insertion of 1 amino acid(s) of the BRCA2 protein (p.Glu2863dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 182323). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 15, 2019 | Variant summary: BRCA2 c.8588_8590dupAAG (p.Glu2863dup) causes an in-frame duplication, which is predicted to be a polymorphism by mutation taster, although this prediction has yet to be functionally assessed. The variant was absent in 251178 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.8588_8590dupAAG in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with another pathogenic variant from reputable database have been reported (BRCA2 c.631+2T>G, KConFab), providing supporting evidence for a benign role. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at