Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1PM2BP4_ModerateBP6
The NM_007294.4(BRCA1):c.5285G>A(p.Arg1762Lys) 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. 14/21 in silico tools predict a benign 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. R1762G) 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 1 ACMG points.
PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 17 uncertain in NM_007294.4
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.096331984).
BP6
Variant 17-43051110-C-T is Benign according to our data. Variant chr17-43051110-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 422395.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Uncertain_significance=1, Likely_benign=1}.
Uncertain significance, criteria provided, single submitter
clinical testing
GeneDx
Sep 30, 2016
This variant is denoted BRCA1 c.5285G>A at the cDNA level, p.Arg1762Lys (R1762K) at the protein level, and results in the change of an Arginine to a Lysine (AGG>AAG). Using alternate nomenclature, this variant would be defined as BRCA1 5404G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Arg1762Lys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Lysine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Arg1762Lys occurs at a position that is not conserved and is located in the BRCT2 Domain and a region known to interact with multiple other proteins (Paul 2014, UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA1 Arg1762Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Nov 05, 2019
This alteration is classified as likely 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