rs80357717
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000357654.9(BRCA1):c.2707_2708insAT(p.Cys903TyrfsTer98) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,896 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
BRCA1
ENST00000357654.9 frameshift
ENST00000357654.9 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.330
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 Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43092823-C-CAT is Pathogenic according to our data. Variant chr17-43092823-C-CAT is described in ClinVar as [Pathogenic]. Clinvar id is 37483.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.2707_2708insAT | p.Cys903TyrfsTer98 | frameshift_variant | 10/23 | ENST00000357654.9 | NP_009225.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.2707_2708insAT | p.Cys903TyrfsTer98 | frameshift_variant | 10/23 | 1 | NM_007294.4 | ENSP00000350283 | P4 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152178Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250830Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135516
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461718Hom.: 0 Cov.: 46 AF XY: 0.00000275 AC XY: 2AN XY: 727136
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74324
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:14
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 30, 2023 | - - |
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 | Sharing Clinical Reports Project (SCRP) | Mar 31, 2010 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | Nov 19, 2018 | This frameshifting variant in exon 10 of 24 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function. This variant is reported as a pathogenic variant in a single publication (PMID: 28152038) and multiple clinical diagnostic laboratories in ClinVar have classified this variant as a pathogenic change for hereditary breast and ovarian cancer syndrome (Variation ID: 37483). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0008% (2/250830) and thus is presumed to be rare. Based on the available evidence, the c.2706_2707dup (p.Cys903TyrfsTer98) variant is classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
Pathogenic, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Sep 08, 2016 | Variant allele predicted to encode a truncated non-functional protein. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jun 03, 2015 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 17, 2021 | This variant inserts 2 nucleotides in exon 10 of the BRCA1 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 identified in 2/250830 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 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 | curation | Sema4, Sema4 | Apr 23, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 05, 2021 | The c.2706_2707dupAT pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of AT at nucleotide position 2706, causing a translational frameshift with a predicted alternate stop codon (p.C903Yfs*98). 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. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 23, 2022 | This frameshift variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. The frequency of this variant in the general population, 0.000018 (2/113274 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in an individual with breast and/or ovarian cancer (PMID: 31447099 (2019)), as well as in an individual with a paraganglioma (PMID: 29625052 (2018)). Based on the available information, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 06, 2024 | 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; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 2825insAT, 2825_2826insAT, 2825_2826dupAT; Observed in an individual with a paraganglioma in the published literature (PMID: 29625052); This variant is associated with the following publications: (PMID: 28152038, 29922827, 29625052, 31447099, 30720243) - |
Hereditary breast ovarian cancer syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2024 | This sequence change creates a premature translational stop signal (p.Cys903Tyrfs*98) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs80357717, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 37483). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 15, 2021 | The p.Cys903TyrfsX98 variant in BRCA1 has been reported in at least 2 individuals with hereditary breast and ovarian cancer (HBOC; Breast Cancer Information Core (BIC) database: https://research.nhgri.nih.gov/bic/, Rady Children's Hospital: ClinVar SCV000996213.1). This variant has also been identified in 0.001% (1/68030) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 903 and leads to a premature termination codon 98 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism for HBOC. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP criteria applied: PS4_Supporting, PM2_supporting, PVS1. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at