ClinVar Genomic variation as it relates to human health

The p.N356I variant (also known as c.1067A>T), located in coding exon 4 of the BARD1 gene, results from an A to T substitution at nucleotide position 1067. The asparagine at codon 356 is replaced by isoleucine, an amino acid with dissimilar properties. Functional analyses demonstrates that this variant retains 65% homology-directed repair function compared to wild-type (Lee C et al. Hum Mutat, 2015 Dec;36:1205-14). In a study of 196 women with breast cancer and 185 unaffected controls from Cameroon and Uganda, this variant was observed in two women, but the authors did not specify if they were in the case or control group (Adedokun B et al. Cancer Epidemiol Biomarkers Prev, 2020 02;29:359-367). This variant was identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This amino acid position is not well 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.

This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 356 of the BARD1 protein (p.Asn356Ile). This variant is present in population databases (rs577834428, gnomAD 0.01%). This missense change has been observed in individual(s) with with clinical features of hereditary breast and ovarian cancer syndrome (PMID: 26350354). ClinVar contains an entry for this variant (Variation ID: 141035). 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 tolerated. Experimental studies have shown that this missense change does not substantially affect BARD1 function (PMID: 26350354). 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 denoted BARD1 c.1067A>T at the cDNA level, p.Asn356Ile (N356I) at the protein level, and results in the change of an Asparagine to an Isoleucine (AAT>ATT). This variant was classified as functional based on a homology-directed repair assay (Lee 2015). BARD1 Asn356Ile was not observed at a significant allele frequency in 1000 genomes. Since Asparagine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BARD1 Asn356Ile occurs at a position that is not conserved and is not located in a known functional domain (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 BARD1 Asn356Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

This missense variant replaces asparagine with isoleucine at codon 356 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). A functional study has shown this variant has intermediate activity in a homology-mediated DNA repair assay (PMID: 26350354). This variant has been reported in an individual affected with breast cancer (PMID: 33471991; Leiden Open Variation Database DB-ID BARD1_000315). This variant has been identified in 3/251282 chromosomes 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.