Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_007294.4(BRCA1):c.139T>C(p.Cys47Arg) variant causes a missense 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C47Y) has been classified 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]
BRCA1 Gene-Disease associations (from GenCC):
breast-ovarian cancer, familial, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Our verdict: Pathogenic. The variant received 18 ACMG points.
PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 16 uncertain in NM_007294.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-43106528-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 54246.Status of the report is reviewed_by_expert_panel, 3 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.986
PP5
Variant 17-43106529-A-G is Pathogenic according to our data. Variant chr17-43106529-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 651975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Hereditary breast ovarian cancer syndromePathogenic:2
Jan 04, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 47 of the BRCA1 protein (p.Cys47Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast, lung, gastric and other cancers (PMID: 30032850). ClinVar contains an entry for this variant (Variation ID: 651975). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 22843421, 25823446, 30209399). This variant disrupts the p.Cys47 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12698193, 21922593, 25823446, 27495310, 29339979, 29446198, 30209399). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
May 01, 2020
Breast Center, Key Laboratory of Carcinogenesis and Translational Research
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
Breast-ovarian cancer, familial, susceptibility to, 1Pathogenic:1
May 24, 2021
Molecular Oncology, Hospital Universitario Central de Asturias (HUCA)