Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The ENST00000591534.5(BRCA1):c.-20C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. 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 (★★★).
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 12 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
BayesDel_addAF computational evidence supports a deleterious effect, 0.358
PP5
Variant 17-43074498-G-C is Pathogenic according to our data. Variant chr17-43074498-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 440476.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43074498-G-C is described in Lovd as [Pathogenic]. Variant chr17-43074498-G-C is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:2
Mar 02, 2020
BRCAlab, Lund University
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Dec 15, 2017
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Significance: Pathogenic
Review Status: reviewed by expert panel
Collection Method: curation
Variant allele predicted to encode a truncated non-functional protein. -
Hereditary breast ovarian cancer syndrome Pathogenic:2
Jul 29, 2019
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Variant summary: BRCA1 c.4508C>G (p.Ser1503X; legacy name : c.4627C>G) 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 251308 control chromosomes (gnomAD). c.4508C>G has been reported in the literature in an individual affected with Hereditary Breast and Ovarian Cancer (Bhaskaran_2019). In addition, a different nucleotide change (c.4508C>A) resulting in the same codon change (p.Ser1503X) has been reported in several families affected with breast and/or ovarian cancer (Rashid_2006). p.Ser1503X is reported in the literature to be a founder mutation in Pakistani population (Shanmughapriya _2013, Ferla _2007, Wu _2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three submitters, including one expert panel (ENIGMA), have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Dec 13, 2020
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 30702160). ClinVar contains an entry for this variant (Variation ID: 440476). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser1503*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. -
not provided Pathogenic:1
Sep 15, 2016
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter