Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3
The NM_007294.4(BRCA1):c.98A>C(p.Glu33Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. E33D) has been classified as Uncertain significance.
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 Uncertain_significance. Variant got 5 ACMG points.
PM1
?
PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 17 uncertain in NM_007294.4
PM2
?
PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP3
?
PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
MetaRNN computational evidence supports a deleterious effect, 0.763
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Other:1
Uncertain significance, criteria provided, single submitter
clinical testing
All of Us Research Program, National Institutes of Health
Dec 18, 2023
This missense variant replaces glutamic acid with alanine at codon 33 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant does not impact BRCA1 function in a homology-directed repair, a BARD1 binding, a ubiquitin ligase and a haploid cell proliferation assay (PMID: 25823446, 30209399, 30219179). This variant has been reported in a suspected hereditary breast cancer family (PMID: 15131401). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter
clinical testing
Ambry Genetics
Mar 26, 2022
The p.E33A variant (also known as c.98A>C), located in coding exon 2 of the BRCA1 gene, results from an A to C substitution at nucleotide position 98. The glutamic acid at codon 33 is replaced by alanine, an amino acid with dissimilar properties. This alteration has been identified in several breast cancer families (Muller D et al. Fam. Cancer, 2004;3:15-20; Martelotto LG et al. Genome Biol., 2014 Oct;15:484). This alteration was partially functional in a yeast-based assay but showed wild-type like function in multiple other assays (Millot GA et al. Hum. Mutat., 2011 Dec;32:1470-80; Starita LM et al. Am. J. Hum. Genet., 2018 10;103:498-508; Findlay GM et al. Nature, 2018 10;562:217-222; Starita LM et al. Genetics, 2015 Jun;200:413-22). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Invitae
Jan 12, 2017
This sequence change replaces glutamic acid with alanine at codon 33 of the BRCA1 protein (p.Glu33Ala). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in an individual affected with breast and/or ovarian cancer (PMID: 15131401). ClinVar contains an entry for this variant (Variation ID: 234092). One experimental study performed in yeast cells has shown that this missense change had a detrimental effect on protein function for cell survival in vitro (PMID: 21922593). In summary, this variant is a rare missense change with a deleterious effect on protein function in vitro. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Loss of ubiquitination at K32 (P = 0.0877);Loss of ubiquitination at K32 (P = 0.0877);Loss of ubiquitination at K32 (P = 0.0877);Loss of ubiquitination at K32 (P = 0.0877);Loss of ubiquitination at K32 (P = 0.0877);Loss of ubiquitination at K32 (P = 0.0877);Loss of ubiquitination at K32 (P = 0.0877);Loss of ubiquitination at K32 (P = 0.0877);Loss of ubiquitination at K32 (P = 0.0877);Loss of ubiquitination at K32 (P = 0.0877);Loss of ubiquitination at K32 (P = 0.0877);Loss of ubiquitination at K32 (P = 0.0877);Loss of ubiquitination at K32 (P = 0.0877);