ClinVar Genomic variation as it relates to human health

The p.Y736F variant (also known as c.2207A>T), located in coding exon 11 of the BARD1 gene, results from an A to T substitution at nucleotide position 2207. The tyrosine at codon 736 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

This variant is denoted BARD1 c.2207A>T at the cDNA level, p.Tyr736Phe (Y736F) at the protein level, and results in the change of a Tyrosine to a Phenylalanine (TAT>TTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BARD1 Tyr736Phe 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 Tyrosine and Phenylalanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BARD1 Tyr736Phe occurs at a position that is highly conserved across species and is located within the BRCT2 domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BARD1 Tyr736Phe is pathogenic or benign. We consider it to be a variant of uncertain significance.

This missense variant replaces tyrosine with phenylalanine at codon 736 of the BARD1 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 BARD1-related disorders in the literature. 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.

This sequence change replaces tyrosine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 736 of the BARD1 protein (p.Tyr736Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BARD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 127733). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.