Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1PM2PP3BP6
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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E33Q) 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]
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: Uncertain_significance. The variant received 4 ACMG points.
PM1
In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 16 uncertain in NM_007294.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.763
BP6
Variant 17-43115762-T-G is Benign according to our data. Variant chr17-43115762-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 234092.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
33476
American (AMR)
AF:
0.00
AC:
0
AN:
44680
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26112
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39670
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86196
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53392
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1111768
Other (OTH)
AF:
0.00
AC:
0
AN:
60376
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
0
ClinVar
Significance: Conflicting classifications of pathogenicity
Breast-ovarian cancer, familial, susceptibility to, 1Uncertain:1Benign:1
Apr 12, 2024
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:curation
Each variant was annotated with functional scores from MAVE data which was translated into functional evidence codes. All other evidence codes and combining criteria were adhered to as closely as possible based on the ClinGen VCEP (Variant Curation Expert Panel) gene-specific recommendations. See Supplemental Figure 34 of final paper (Supp Fig. 28 in preprint: doi:10.1101/2024.04.11.24305690) for a table to see which lines of evidence we did not have data for. The ClinGen VCEPs are highly regarded as the gold-standard for gene-specific variant curation and are developed after extensive evaluation of the evidence by clinical and scientific experts for the particular gene to classify genomic variants on a spectrum from pathogenic to benign using the 2015 ACMG/AMP Variant Interpretation Guidelines as a backbone (PMID: 25741868). Reclassification of these VUS variants from gnomAD or All of Us focused only on variants originally prescribed as VUS in ClinVar. To ensure reproducibility, transparency, and increased throughput, all the procedures for annotating variants and assigning evidence codes were codified using Python. All code has been made freely available and is linked in the Code Availability section and all reclassified variants with evidence codes used can be found in Tables S18-19 (preprint: doi:10.1101/2024.04.11.24305690). For the MAVE data, the clinical curation and clinical strength assignment as per the ClinGen recommendations in Brnich et al. (2020) (PMID: 31892348) for or against pathogenicity or benignity of each of these MAVE datasets utilized in this study were previously published in Fayer et al. (2021) (PMID: 34793697).In brief, for BRCA1 variants, if a variant was categorized as FUNC (functional), it was assigned BS3 evidence and no PS3 evidence, whereas if it was categorized as LOF (loss of function), the variant was assigned PS3 evidence and no BS3 evidence. Variants categorized as INT (intermediate) were left unannotated. For the BRCA1 combining criteria, greater than or equal to 1 criteria of strong benign evidence was enough to reclassify the VUS as Likely Benign. This variant GRCh38:17:43115762:T>G was assigned evidence codes ['BS3'] and an overall classification of Likely benign -
Dec 18, 2023
All of Us Research Program, National Institutes of Health
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
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. -
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 syndromeUncertain:1
Jan 12, 2017
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing
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. 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). 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). This variant is not present in population databases (ExAC no frequency). 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. -
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);