rs80358331
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PM4_SupportingBP6
The NM_007294.4(BRCA1):βc.2483_2485delβ(p.Gly828_Phe829delinsVal) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,774 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 32)
Exomes π: 6.8e-7 ( 0 hom. )
Consequence
BRCA1
NM_007294.4 inframe_deletion
NM_007294.4 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.147
Genes affected
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
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Very rare variant in population databases, with high coverage;
PM4
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Nonframeshift variant in NON repetitive region in NM_007294.4. Strenght limited to Supporting due to length of the change: 1aa.
BP6
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Variant 17-43093045-AAGC-A is Benign according to our data. Variant chr17-43093045-AAGC-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 54582.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=9, Likely_benign=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.2483_2485del | p.Gly828_Phe829delinsVal | inframe_deletion | 10/23 | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.2483_2485del | p.Gly828_Phe829delinsVal | inframe_deletion | 10/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152144Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 250982Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135652
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461630Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 727120
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:10Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 13, 2024 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | Jun 20, 2002 | - - |
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Oct 02, 2023 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 17, 2017 | - - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 02, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 06, 2023 | The c.2483_2485delGCT variant (also known as p.G828_F829delinsV) is located in coding exon 9 of the BRCA1 gene. This variant results from an in-frame deletion of GCT at nucleotide positions 2483 to 2485. This results in the deletion of the glycine residue at codon 828 and the phenylalanine residue at codon 829 and the insertion of a valine residue. This alteration was previously identified in 1/1398 unilateral breast cancer cases and 0/705 bilateral breast cancer cases in a population based study (Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40). It has also been reported in a series of over 50000 patients undergoing BRCA1 sequencing (Judkins T et al. Cancer Res. 2005 Nov;65:10096-103). This amino acid region 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. - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 11, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 23, 2018 | Variant summary: BRCA1 c.2483_2485delGCT (p.Gly828_Phe829delinsVal) results in an in-frame deletion that is predicted to remove 2 amino acids from the encoded protein and add one. The variant allele was found at a frequency of 7.2e-06 in 276710 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2483_2485delGCT has been reported in affected individuals in the literature, without strong evidence for causality (Borg_2010, Judkins_2005). BIC (Breast Cancer Information Core) database cites the variant in an individual who carries a common pathogenic variant in BRCA1 (c.181T>G, p.Cys61Gly), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 20, 2022 | The BRCA1 c.2483_2485delGCT; p.Gly828_Phe829delinsVal variant (rs80358331) is reported in the literature in an individual affected with breast cancer, but without clear disease association (Borg 2010). This variant is also reported in ClinVar (Variation ID: 54582), but is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant deletes 3 nucleotides, which would replace a glycine and phenylalanine with valine, leaving the rest of the protein in-frame. Due to limited information, the clinical significance of this variant is uncertain at this time. References: Borg A et al. Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. Hum Mutat. 2010 Mar;31(3):E1200-40. PMID: 20104584. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 01, 2021 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In-frame deletion of 2 amino acids and insertion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Also known as 2602_2604delGCT; This variant is associated with the following publications: (PMID: 20104584, 16267036) - |
BRCA1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 01, 2024 | The BRCA1 c.2483_2485delGCT variant is predicted to result in an in-frame deletion (p.Gly828_Phe829delinsVal). This variant has been reported in an individual with breast cancer (Table S2 - Borg et al. 2010. PubMed ID: 20104584) and an individual with breast and/or ovarian cancer (referred to as G828del - Judkins et al. 2005. PubMed ID: 16267036). This variant is reported in 0.0016% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of pathogenicity of likely benign and uncertain in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/54582/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This variant, c.2483_2485del, is a complex sequence change that results in the deletion of 2 and insertion of 1 amino acid(s) in the BRCA1 protein (p.Gly828_Phe829delinsVal). This variant is present in population databases (rs80358331, gnomAD 0.002%). This variant has been observed to co-occur in individuals with a different variant in BRCA1 that has been determined to be pathogenic (PMID: 10923033, 20104584), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 54582). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
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