Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_007294.4(BRCA1):c.201T>G(p.Asp67Glu) 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 benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D67Y) has been classified as Benign.
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]
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Other:1
Uncertain significance, no assertion criteria provided
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
Jun 27, 2002
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not provided, no classification provided
in vitro
Brotman Baty Institute, University of Washington
-
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not provided Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Jun 14, 2016
Variant summary: The BRCA1 c.201T>G (p.Asp67Glu) variant involves the alteration of a non-conserved nucleotide and results in a replacement of an Aspartic acid (D) with a Glutamic acid (E). Both of the residues are medium size and acidic, therefore, this Asp to Glu substitution likely does not alter the physico-chemical properties of the BRCA1 protein. Consistently, 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 118118 control chromosomes while it was reported in three HBOC patients; two of whom had family history of the disease. The variant is located in the central RING domain of BRCA1, in the vicinity of Zn2+ binding site II. Based on a BRCA1 RING model, the Asp67 residue is on the surface of the RING domain and has a side chain with extended orientations favorable for interaction with other proteins. It has been suggested that mutations of this residues would probe the BRCA1 zinc ring domain functionality as a mediator of protein-protein interactions (Bienstock_CanRes_1996). However, experimental studies found that the D67E variant retains the ligase, metal binding and HDR activity of the BRCA1, does not impact BARD1 and UbcH5a binding, barely perturbs BRCA1s native global structure, and only slightly reduced its thermal stability. It has also been shown to slightly inhibit estrogen receptor signaling pathway. The functional studies indicate the variant to be in the neutral spectrum, however, the possibility of an unknown mechanism by which the variant increases the risk of HBOC cannot be excluded, and therefore, it was classified as a variant of uncertain significance until more information becomes available. -
Gain of disorder (P = 0.1038);Gain of disorder (P = 0.1038);Gain of disorder (P = 0.1038);Gain of disorder (P = 0.1038);.;Gain of disorder (P = 0.1038);Gain of disorder (P = 0.1038);.;Gain of disorder (P = 0.1038);Gain of disorder (P = 0.1038);Gain of disorder (P = 0.1038);Gain of disorder (P = 0.1038);Gain of disorder (P = 0.1038);.;