Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.2762del(p.Gln921ArgfsTer79) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,792 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. Q921Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
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]
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
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PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP5
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PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 17-43092768-CT-C is Pathogenic according to our data. Variant chr17-43092768-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 54674.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43092768-CT-C is described in Lovd as [Pathogenic]. Variant chr17-43092768-CT-C is described in Lovd as [Pathogenic].
The c.2762delA pathogenic mutation (also known as 2881delA), located in coding exon 9 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 2762, causing a translational frameshift with a predicted alternate stop codon. This alteration has been reported in multiple breast and/or ovarian cancer families of Czech ancestry (Machackova E, BMC Cancer 2008 ; 8:140). In addition to the clinical data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -
Pathogenic, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Oct 25, 2021
This variant deletes 1 nucleotide 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 reported in at least one individual and a family affected with breast or ovarian cancer and has been identified in a family among the CIMBA participants (PMID: 15024741, 18489799, 29446198). This variant has not been identified 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. -
Breast and/or ovarian cancer Pathogenic:1
Pathogenic, no assertion criteria provided
clinical testing
CZECANCA consortium
Jun 11, 2019
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not provided Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
GeneDx
Mar 17, 2022
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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Foretova 2004, Machackova 2008); 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 2881delA; This variant is associated with the following publications: (PMID: 18489799, 15024741, 32295079, 29446198, 31409081, 20104584, 32438681) -
Hereditary breast ovarian cancer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Invitae
Jan 01, 2023
This premature translational stop signal has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 15024741, 18489799, 29446198). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln921Argfs*79) 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). ClinVar contains an entry for this variant (Variation ID: 54674). For these reasons, this variant has been classified as Pathogenic. -