Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1PM2BP4_ModerateBP6
The ENST00000357654.9(BRCA1):c.134A>G(p.Lys45Arg) variant causes a missense, splice region 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. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. K45Q) 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]
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM1
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 17 uncertain in ENST00000357654.9
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.2415387).
BP6
Variant 17-43115726-T-C is Benign according to our data. Variant chr17-43115726-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 865152.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, not_provided=1, Uncertain_significance=1}.
Uncertain significance, no assertion criteria provided
clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System
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The BRCA1 p.Lys45Arg variant was not identified in the literature nor was it identified in the dbSNP, ClinVar, LOVD 3.0 or UMD-LSDB databases. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The variant was demonstrated to have no effect on BRCA1/BARD1 heterodimer activity as demonstrated by a ubiquitin-ligase activity assay (Brzovic 2003). The p.Lys45 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The p.Lys45Arg variant occurs in the last base of the exon, which has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. In addition, 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Oct 09, 2021
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 12732733, 30209399). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 865152). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with arginine at codon 45 of the BRCA1 protein (p.Lys45Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. -
Hereditary cancer-predisposing syndrome Benign:1
Benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Jul 19, 2021
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Breast-ovarian cancer, familial, susceptibility to, 1 Other:1
Loss of methylation at K45 (P = 9e-04);Loss of methylation at K45 (P = 9e-04);Loss of methylation at K45 (P = 9e-04);Loss of methylation at K45 (P = 9e-04);Loss of methylation at K45 (P = 9e-04);Loss of methylation at K45 (P = 9e-04);Loss of methylation at K45 (P = 9e-04);Loss of methylation at K45 (P = 9e-04);Loss of methylation at K45 (P = 9e-04);Loss of methylation at K45 (P = 9e-04);Loss of methylation at K45 (P = 9e-04);Loss of methylation at K45 (P = 9e-04);Loss of methylation at K45 (P = 9e-04);