ClinVar Genomic variation as it relates to human health

This missense variant replaces serine with leucine at codon 760 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 hereditary cancer in the literature. This variant has been identified in 4/251226 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.

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 760 of the BARD1 protein (p.Ser760Leu). This variant is present in population databases (rs730881425, gnomAD 0.003%). 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: 479129). 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.

The p.S760L variant (also known as c.2279C>T), located in coding exon 11 of the BARD1 gene, results from a C to T substitution at nucleotide position 2279. The serine at codon 760 is replaced by leucine, an amino acid with dissimilar properties. This alteration was reported in a study of 1297 cases of early-onset breast cancer and 1121 controls (Young EL et al. J. Med. Genet. 2016 Jun;53:366-76). This amino acid position is 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.

The BARD1 p.Ser760Leu variant was identified in 1 of 2594 proband chromosomes (frequency: 0.0004) from individuals or families with early-onset breast cancer (Young 2016). The variant was also identified in the following databases: dbSNP (ID: rs730881425) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Ambry Geneics and Color), and in Cosmic (1x in oesophagus tissue). The variant was not identified in MutDB, or Zhejiang University, databases. The variant was identified in control databases in 4 of 245998 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 33570 chromosomes (freq: 0.00003), European in 3 of 111490 chromosomes (freq: 0.00003); it was not observed in the African, Other, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Ser760 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.