Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.1326T>A(p.Cys442Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,778 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. C442C) 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 17-43094205-A-T is Pathogenic according to our data. Variant chr17-43094205-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 54202.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43094205-A-T is described in Lovd as [Pathogenic]. Variant chr17-43094205-A-T is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:2
Pathogenic, criteria provided, single submitter
clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Oct 02, 2015
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Pathogenic, reviewed by expert panel
curation
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Oct 18, 2016
Variant allele predicted to encode a truncated non-functional protein. -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Jan 05, 2018
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Pathogenic, criteria provided, single submitter
clinical testing
GeneDx
Apr 30, 2015
This pathogenic variant is denoted BRCA1 c.1326T>A at the cDNA level and p.Cys442Ter (C442X) at the protein level. The substitution creates a nonsense variant, which changes a Cysteine to a premature stop codon (TGT>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, also known as BRCA1 1445T>A using alternate nomenclature, has been reported in an individual with a family history of breast and/or ovarian cancer and an individual with multiple primary tumors diagnosed under the age of 60 (Kadouri 2004, Whitworth 2014). This variant is considered pathogenic. -
The p.C442* pathogenic mutation (also known as c.1326T>A), located in coding exon 9 of the BRCA1 gene, results from a T to A substitution at nucleotide position 1326. This changes the amino acid from a cysteine to a stop codon within coding exon 9. This mutation (designated as 1445T>A) was identified in one non-Ashkenazi individual from the UK with a family history of breast or ovarian cancer (Kadouri L et al. Int. J. Cancer 2004 Jan;108:399-403). 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. -
Pathogenic, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Jun 21, 2021
This variant changes 1 nucleotide in exon 10 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been detected in at least three individuals affected with breast or ovarian cancer (PMID: 28145423, 29337092; Color internal data), in an individual affected with multiple primary cancer (PMID: 25248401) and in at least two suspected hereditary breast and ovarian cancer families (PMID: 14648706, 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. -
Hereditary breast ovarian cancer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Oct 06, 2023
Variant summary: BRCA1 c.1326T>A (p.Cys442X) 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 250930 control chromosomes. c.1326T>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Kadouri_2004, Mattocks_2010, Whitworth_2014). 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. The following publications have been ascertained in the context of this evaluation (PMID: 20167696, 25248401, 14648706). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -