Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000206509 | SCV000260263 | uncertain significance | Familial cancer of breast | 2021-08-30 | criteria provided, single submitter | clinical testing | This variant has been observed in individual(s) with ovarian cancer (PMID: 30093976). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with tyrosine at codon 215 of the BARD1 protein (p.Asn215Tyr). The asparagine residue is highly conserved and there is a large physicochemical difference between asparagine and tyrosine. ClinVar contains an entry for this variant (Variation ID: 220032). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. |
| Ambry Genetics | RCV003165490 | SCV003865641 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-12-01 | criteria provided, single submitter | clinical testing | The p.N215Y variant (also known as c.643A>T), located in coding exon 4 of the BARD1 gene, results from an A to T substitution at nucleotide position 643. The asparagine at codon 215 is replaced by tyrosine, an amino acid with dissimilar properties. This alteration has been reported in an individual from a cohort of 1191 cancer index patients who underwent clinical evaluation and testing with multigene panels (Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660). This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). 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. |
| Baylor Genetics | RCV000206509 | SCV004217237 | uncertain significance | Familial cancer of breast | 2023-07-04 | criteria provided, single submitter | clinical testing | |
| Department of Pathology and Laboratory Medicine, |
RCV001358496 | SCV001554245 | uncertain significance | Malignant tumor of breast | no assertion criteria provided | clinical testing | The BARD1 p.Asn215Tyr variant was identified in 1 of 2382 proband chromosomes (frequency: 0.0004) from individuals with primary cancer (Chan 2018, 30093976). The proband above had ovarian cancer at age 43 and a family history of breast and ovarian cancer although segregation analysis was not performed. The variant was also identified in ClinVar (as Uncertain Significance by Invitae 2016). The variant was identified in control databases in 1 of 227416 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European Non-Finnish in 1 of 106104 chromosomes (freq: 0.000009), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Asn215 residue is conserved in mammals but not in more distantly related organisms, and four out of five 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. |