Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.69_70insAG(p.Cys24SerfsTer8) 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. E23E) has been classified as Likely benign.
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 located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 3499 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43124027-A-ACT is Pathogenic according to our data. Variant chr17-43124027-A-ACT is described in ClinVar as [Pathogenic]. Clinvar id is 55667.Status of the report is reviewed_by_expert_panel, 3 stars.
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:4
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. -
Pathogenic, criteria provided, single submitter
clinical testing
Baylor Genetics
Nov 17, 2023
- -
Pathogenic, no assertion criteria provided
clinical testing
Sharing Clinical Reports Project (SCRP)
Jan 25, 2011
- -
Pathogenic, no assertion criteria provided
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
May 29, 2002
- -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Jul 30, 2019
The BRCA1 c.68_69dup (p.Cys24Serfs*8) variant alters the translational reading frame of the BRCA1 mRNA and causes the premature termination of BRCA1 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 20104584 (2010), 26543556 (2015), and 30262796 (2018)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter
clinical testing
GeneDx
Feb 10, 2017
This duplication of two nucleotides in BRCA1 is denoted c.68_69dupAG at the cDNA level and p.Cys24SerfsX8 (C24SfsX8) at the protein level. Using alternate nomenclature, this variant would also be defined as BRCA1 187_188dupAG or 69_70insAG. The normal sequence, with the bases that are duplicated in brackets, is TTAG[dupAG]TGTC. The duplication causes a frameshift which changes a Cysteine to a Serine at codon 24, and creates a premature stop codon at position 8 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.68_69dupAG has been published in association with at least three cases of breast cancer (Borg 2010, Dean 2015). We consider this variant to be pathogenic. -
Hereditary breast ovarian cancer syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
May 23, 2019
Variant summary: BRCA1 c.68_69dupAG (p.Cys24SerfsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251050 control chromosomes (gnomAD). c.68_69dupAG has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Borg_2010, Dean_2015, Judkins_2005, Quezada Urban_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters including an expert panel (ENIGMA) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter
clinical testing
Invitae
Nov 24, 2023
This sequence change creates a premature translational stop signal (p.Cys24Serfs*8) 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 contralateral breast cancer (PMID: 20104584). ClinVar contains an entry for this variant (Variation ID: 55667). For these reasons, this variant has been classified as Pathogenic. -
Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Pathogenic:1
The c.68_69dupAG pathogenic mutation, located in coding exon 1 of the BRCA1 gene, results from a duplication of AG at nucleotide position 68, causing a translational frameshift with a predicted alternate stop codon (p.C24Sfs*8). This alteration has been reported in several breast cancer patients (Borg A et al. Hum. Mutat., 2010 Mar;31:E1200-40; Dean M et al. Gigascience, 2015 Nov;4:50; Quezada Urban R et al. Cancers (Basel), 2018 Sep;10:; Millan Catalan O et al. Cancers (Basel), 2019 Aug;11:). Of note, this alteration is also designated as 188insAG in published literature. 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. -