Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.5417delC(p.Pro1806GlnfsTer28) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★).
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
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 69 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43047692-TG-T is Pathogenic according to our data. Variant chr17-43047692-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 37669.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43047692-TG-T is described in Lovd as [Pathogenic]. Variant chr17-43047692-TG-T is described in Lovd as [Pathogenic].
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.5417delC pathogenic mutation, located in coding exon 21 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 5417, causing a translational frameshift with a predicted alternate stop codon (p.P1806Qfs*28). This alteration occurs at the 3' terminus of theBRCA1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 28 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration has been identified in an individual diagnosed with breast cancer (Foley SB et al. EBioMedicine 2015 Jan;2(1):74-81). This alteration is also known as 5536delC in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Jun 23, 2020
Color Diagnostics, LLC DBA Color Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant deletes 1 nucleotide in exon 22 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. To our knowledge, 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). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Familial cancer of breast Pathogenic:1
May 02, 2023
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Hereditary breast ovarian cancer syndrome Pathogenic:1
May 03, 2020
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This sequence change results in a premature translational stop signal in the BRCA1 gene (p.Pro1806Glnfs*28). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 58 amino acids of the BRCA1 protein. A different truncation (p.Gln1857Argfs*65) that lies downstream of this variant has been determined to be pathogenic (PMID: 21520333, 11573086, 14576433, 15133503, 25652403). This suggests that deletion of this region of the BRCA1 protein is likely to be causative of disease. This variant is expected to disrupt a portion of the C-terminal region of the BRCA1 protein containing the BRCT domain (residues Val1646-Pro1859) (PMID: 25652403). Although functional studies have not been performed for this particular variant, the BRCT domain is critical for BRCA1 DNA repair activity (PMID: 11573086, 14576433, 15133503, 25652403). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has been observed in an individual affected with breast cancer (PMID: 26023681). This variant is also known as 5536delC (p.P1759fs) in the literature. ClinVar contains an entry for this variant (Variation ID: 37669). This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. -