BRCA1 NM_007294.3:c.5200T>A, Phe1734Ile

The p.F1734I pathogenic mutation (also known as c.5200T>A), located in coding exon 18 of the BRCA1 gene, results from a T to A substitution at nucleotide position 5200. The phenylalanine at codon 1734 is replaced by isoleucine, an amino acid with highly similar properties. One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Based on internal structural analysis, F1734I decreases the structure stability (Wu Q et al. Mol Cell, 2016 Feb;61:434-448). Another alteration at the same codon, p.F1734L (c.5202T>G), has been also been found to be non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222) and based on internal structural analysis, F1734L decreases the structure stability (Wu Q et al. Mol Cell, 2016 Feb;61:434-448). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

This missense variant replaces phenylalanine with isoleucine at codon 1734 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 impacts BRCA1 function in a homology-directed DNA repair assay and in a haploid cell proliferation assay (PMID: 30209399, 35196514). This variant has been detected in one individual each affected with ovarian and breast cancer (PMID: 32776218; Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1734 of the BRCA1 protein (p.Phe1734Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ovarian cancer (PMID: 32776218). ClinVar contains an entry for this variant (Variation ID: 232047). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 30209399, 35196514). 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 variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 30209399, 35196514].

It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in an affected individual with ovarian cancer (PMID: 32776218 (2020)). A saturation genome editing assay found this variant to be non-functional in homology-directed DNA repair (PMID: 30209399 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.