ClinVar Genomic variation as it relates to human health

This variant is denoted BRCA2 c.5575A>G at the cDNA level, p.Ile1859Val (I1859V) at the protein level, and results in the change of an Isoleucine to a Valine (ATT>GTT). Using alternate nomenclature, this variant would be defined as BRCA2 5803A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ile1859Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Ile1859Val occurs at a position that is not conserved and is located in the 6th BRC repeat domain and RAD51 binding region (Roy 2012, UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Ile1859Val is pathogenic or benign. We consider it to be a variant of uncertain significance.

To our knowledge, this sequence variant has not been previously reported in the literature. This variant is not present in population databases (https://gnomad.broadinstitute.org/). In silico analyses indicate that this variant does not alter protein structure/function. Thus, it is unknown at this time whether this variant increases cancer risk. PM2; BP4

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).

This missense variant replaces isoleucine with valine at codon 1859 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BRCA2-related disorders in the literature, but has been observed in an unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008352). 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.

Variant summary: The BRCA2 c.5575A>G (p.Ile1859Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a benign outcome for this variant. This variant is absent in 120450 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. The variant is located in one of the BRCA repeats that is critical for binding to RAD51 (a key protein in DNA recombinational repair) and resistance to methyl methanesulphonate treatment (IPR002093). However, because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.

The BRCA2 c.5575A>G (p.Ile1859Val) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant was detected in 2 of 138,342 individuals who underwent multi-gene panel testing including BRCA1 and BRCA2 and did not have a pathogenic or likely pathogenic variant in another gene related to hereditary breast cancer (PMID: 31853058), as well as in one woman older than 70 years of age who has never had cancer (FLOSSIES, https://whi.color.com/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. In summary, the evidence currently available is insufficient to determine the role of this variant in hereditary breast and ovarian cancer syndrome and/or Fanconi anemia. It has therefore been classified as of uncertain significance.

In the published literature, this variant has been reported to be located in a region of the BRCA2 gene that is tolerant to missense changed (PMID: 31911673 (2020)). In a large-scale breast cancer association study, the variant was observed in an unaffected individual (PMID: 33471991 (2021)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1859 of the BRCA2 protein (p.Ile1859Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 37974). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. 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.

This missense variant replaces isoleucine with valine at codon 1859 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BRCA2-related disorders in the literature, but has been observed in an unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008352). 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.I1859V variant (also known as c.5575A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 5575. The isoleucine at codon 1859 is replaced by valine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.