Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000572668 | SCV000660860 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-12-04 | criteria provided, single submitter | clinical testing | The p.S728F variant (also known as c.2183C>T), located in coding exon 11 of the BARD1 gene, results from a C to T substitution at nucleotide position 2183. The serine at codon 728 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration has been reported as a variant of unknown significance in an individual from a cohort of 488 patients with stages I to III breast cancer (Tung N et al. J Clin Oncol, 2016 May;34:1460-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Color Diagnostics, |
RCV000572668 | SCV000688181 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-01-05 | criteria provided, single submitter | clinical testing | This missense variant replaces serine with phenylalanine at codon 728 of the BARD1 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 26976419). This variant has been identified in 15/251340 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. |
| Invitae | RCV000635794 | SCV000757217 | uncertain significance | Familial cancer of breast | 2024-01-28 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 728 of the BARD1 protein (p.Ser728Phe). This variant is present in population databases (rs13389423, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer (PMID: 26976419). ClinVar contains an entry for this variant (Variation ID: 479142). 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. |
| Neuberg Centre For Genomic Medicine, |
RCV000635794 | SCV002073276 | uncertain significance | Familial cancer of breast | criteria provided, single submitter | clinical testing | The missense variant p.S728F in BARD1 (NM_000465.4) has been previously reported as a variant of uncertain significance in an individual with breast cancer (Tung J et al). The missense variant c.2183C>T (p.S728F) in BARD1 (NM_000465.4) is observed in 15/30616 (0.049%) alleles from individuals of South Asian background in the gnomAD dataset (Exome Aggregation Consortium et al., 2016), but was not seen in the homozygous state.The p.S728F missense variant is predicted to be damaging by both SIFT and PolyPhen2. The serine residue at codon 728 of BARD1 is conserved in all mammalian species. The nucleotide c.2183 in BARD1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. |