rs80359472
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PM4_Supporting
The NM_000059.4(BRCA2):βc.4933_4935delβ(p.Lys1645del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000249 in 1,606,578 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β β ).
Frequency
Genomes: π 0.000020 ( 0 hom., cov: 33)
Exomes π: 6.9e-7 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 inframe_deletion
NM_000059.4 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.07
Genes affected
BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_000059.4. Strenght limited to Supporting due to length of the change: 1aa.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.4933_4935del | p.Lys1645del | inframe_deletion | 11/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.4933_4935del | p.Lys1645del | inframe_deletion | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152096Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000411 AC: 1AN: 243486Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 131790
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GnomAD4 exome AF: 6.88e-7 AC: 1AN: 1454364Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 723146
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152214Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74412
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 13, 2023 | The c.4933_4935delAAA variant (also known as p.K1645del) is located in coding exon 10 of the BRCA2 gene. This variant results from an in-frame AAA deletion at nucleotide positions 4933 to 4935. This results in the in-frame deletion of a lysine at codon 1645. In one study, this variant was detected in 1/80 Portuguese breast and/or ovarian cancer patients who were tested for BRCA1/2 mutations and who did not carry a founder mutation (Pinto P et al. Breast Cancer Res. Treat., 2016 Sep;159:245-56). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (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. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Jul 16, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 29, 2022 | This variant causes a deletion of 1 amino acid, lysine 1645, from the BRCA2 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in an individual affected with early-onset breast cancer, who also carried a pathogenic truncation variant in the BRCA1 gene (PMID:27553368). This variant has been identified in 1/243486 chromosomes 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. - |
Hereditary breast ovarian cancer syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Apr 16, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 12, 2023 | 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 252422). This variant has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 27553368, 32850417). This variant is present in population databases (rs761871715, gnomAD 0.003%). This variant, c.4933_4935del, results in the deletion of 1 amino acid(s) of the BRCA2 protein (p.Lys1645del), but otherwise preserves the integrity of the reading frame. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 11, 2022 | Variant summary: BRCA2 c.4933_4935delAAA (p.Lys1645del) results in an in-frame deletion that is predicted to remove one amino acids from the encoded protein. The variant allele was found at a frequency of 4.1e-06 in 243486 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4933_4935delAAA has been reported in the literature in one individual affected with Breast Cancer (Pinto_2016), however this individual also carried a co-occurring pathogenic variant (BRCA1 c.3817C>T (p.Gln1273Ter)), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other 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 uncertain significance. - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 15, 2023 | This variant causes a deletion of 1 amino acid, lysine 1645, from the BRCA2 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in an individual affected with early-onset breast cancer, who also carried a pathogenic truncation variant in the BRCA1 gene (PMID:27553368). This variant has been identified in 1/243486 chromosomes 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 06, 2023 | The frequency of this variant in the general population, 0.0000041 (1/243486 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with breast cancer who also carried a pathogenic BRCA1 truncating variant (PMID: 27553368 (2016)). The variant has also been reported in an individual with ovarian cancer (PMID: 32850417 (2020)). Based on the available information, we are unable to determine the clinical significance of this variant. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at