Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000357654.9(BRCA1):c.1504_1507del(p.Leu502SerfsTer29) 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. L502L) 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
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 17-43094023-TTTAA-T is Pathogenic according to our data. Variant chr17-43094023-TTTAA-T is described in ClinVar as [Pathogenic]. Clinvar id is 266170.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43094023-TTTAA-T is described in Lovd as [Pathogenic]. Variant chr17-43094023-TTTAA-T is described in Lovd as [Pathogenic].
This variant deletes 4 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 reported in multiple individuals and families affected with breast and ovarian cancer (PMID: 23961350, 29088781, 30103829, 31125277, 34072659), and has been identified in 4 families among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). 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. -
Pathogenic, criteria provided, single submitter
clinical testing
Ambry Genetics
Dec 13, 2023
The c.1504_1507delTTAA pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of 4 nucleotides at nucleotide positions 1504 to 1507, causing a translational frameshift with a predicted alternate stop codon (p.L502Sfs*29). This mutation (designated as c.1502_1505delAATT) has been reported in an Argentinian patient with early onset breast cancer (Solano AR et al. Springerplus 2012;1:20). It has also been identified in two families from a cohort of 453 Chilean patients with hereditary breast cancer (Alvarez C et al. Oncotarget, 2017 Sep;8:74233-74243), 1/398 probands with epithelial ovarian cancer (Cardoso FC et al. Hum. Genomics, 2018 08;12:39), and one patient w/ Argentinian ancestry from a cohort of 315 Chilean patients referred for genetic testing due to suspicion of Hereditary Breast and/or Ovarian Cancer syndrome (Adaniel C et al. J Glob Oncol, 2019 05;5:1-14). In addition to the clinical data presented in the literature, 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. -
Hereditary breast ovarian cancer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Dec 14, 2023
This sequence change creates a premature translational stop signal (p.Leu502Serfs*29) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with a personal and/or family history of breast and ovarian cancer (PMID: 23961350, 29088781, 29446198, 30103829). This variant is also known as c.1502_1505delAATT. ClinVar contains an entry for this variant (Variation ID: 266170). For these reasons, this variant has been classified as Pathogenic. -