Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_007294.4(BRCA1):āc.192T>Gā(p.Cys64Trp) variant causes a missense 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 Likely pathogenic (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C64Y) 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]
Verdict is Pathogenic. Variant got 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 7 benign, 17 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 chr17-43106477-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 54400.Status of the report is reviewed_by_expert_panel, 3 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.987
PP5
Variant 17-43106476-A-C is Pathogenic according to our data. Variant chr17-43106476-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 224427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43106476-A-C is described in Lovd as [Pathogenic]. Variant chr17-43106476-A-C is described in Lovd as [Likely_pathogenic]. Variant chr17-43106476-A-C is described in Lovd as [Likely_pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:2Other:1
Pathogenic, criteria provided, single submitter
clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Oct 02, 2015
- -
Likely pathogenic, criteria provided, single submitter
clinical testing
Mendelics
May 28, 2019
- -
not provided, no classification provided
in vitro
Brotman Baty Institute, University of Washington
-
- -
Breast neoplasm Pathogenic:1
Likely pathogenic, criteria provided, single submitter
research
Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University
Nov 01, 2015
- -
Hereditary breast ovarian cancer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Invitae
Apr 18, 2021
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys64 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15131401, 22034289, 23397983, 18489799, 19949876, 25085752, 19287957, 24516540, 23867111, 23161852, 12915465, 23161852, 23867111, 7894491, 21042765). This suggests that this residue is clinically-significant, and that variants that disrupt this residue are likely to be disease-causing. This variant affects the highly conserved Cys64 residue within the N-terminal RING domain of the BRCA1 protein (PMID: 22843421).Ā¬ā This variant has been reported to affect BRCA1 protein function (PMID:Ā¬ā 30209399). This variant has been observed in an individual affected with breast cancer (PMID: 27257965), and in a family with breast cancer (PMID: 29446198). ClinVar contains an entry for this variant (Variation ID: 224427). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tryptophan at codon 64 of the BRCA1 protein (p.Cys64Trp). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tryptophan. -
Loss of disorder (P = 0.0243);Loss of disorder (P = 0.0243);Loss of disorder (P = 0.0243);Loss of disorder (P = 0.0243);.;Loss of disorder (P = 0.0243);Loss of disorder (P = 0.0243);.;Loss of disorder (P = 0.0243);Loss of disorder (P = 0.0243);Loss of disorder (P = 0.0243);Loss of disorder (P = 0.0243);Loss of disorder (P = 0.0243);.;