Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.1969C>T(p.Gln657Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. Q657Q) has been classified as 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 17-43093562-G-A is Pathogenic according to our data. Variant chr17-43093562-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 54423.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43093562-G-A is described in Lovd as [Pathogenic]. Variant chr17-43093562-G-A is described in Lovd as [Pathogenic].
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Oct 18, 2016
Variant allele predicted to encode a truncated non-functional protein. -
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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Hereditary breast ovarian cancer syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Nov 07, 2023
This sequence change creates a premature translational stop signal (p.Gln657*) 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 breast cancer (PMID: 16826315, 30720863). ClinVar contains an entry for this variant (Variation ID: 54423). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Apr 25, 2021
Variant summary: BRCA1 c.1969C>T (p.Gln657X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251128 control chromosomes. c.1969C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Judkins_2005, Deng_2019, Peixoto_2014, Rebbeck_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One expert panel (ENIGMA) and one consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Ovarian carcinoma Pathogenic:1
Pathogenic, no assertion criteria provided
clinical testing
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences
Sep 12, 2021
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not provided Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
GeneDx
Oct 24, 2014
This mutation is noted BRCA1 c.1969C>T at the cDNA level and p.Gln657Ter (Q657X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in association with hereditary breast cancer and is considered pathogenic (Peixoto 2006). -