Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000570342 | SCV000665866 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2016-09-07 | criteria provided, single submitter | clinical testing | The p.A1843P variant (also known as c.5527G>C), located in coding exon 22 of the BRCA1 gene, results from a G to C substitution at nucleotide position 5527. The alanine at codon 1843 is replaced by proline, an amino acid with highly similar properties. This variant was previously detected in a Japanese female with a personal and family history of ovarian cancer (Sekine M et al Clin Cancer Res. 2001; 7(10):3144-50). Functional studies have demonstrated that this variant, which is located in the BRCT domain, results in a moderately destabilizing protein (Rowling PJ et al. J. Biol. Chem., 2010 Jun;285:20080-7; Lee MS et al. Cancer Res., 2010 Jun;70:4880-90). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Clapperton JA et al. Nat Struct Mol Biol. 2004; 11(6):512-8; Ambry Internal Data). This variant was previously reported in the SNPDatabase as rs80357019, but was absent from population-based cohorts in the NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project databases. To date, this alteration has been detected with an allele frequency of approximately 0.0003% (greater than 300000 alleles tested) in our clinical cohort. This amino acid position is well conserved in available vertebrate species. In addition, this variant is predicted to be possibly damaging and deleterious by PolyPhen and SIFT, as well as other various in silico tools (Mirkovic N et al. Cancer Res., 2004 Jun;64:3790-7). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000781015 | SCV000918767 | likely pathogenic | Hereditary breast ovarian cancer syndrome | 2018-08-13 | criteria provided, single submitter | clinical testing | Variant summary: BRCA1 c.5527G>C (p.Ala1843Pro) results in a non-conservative amino acid change located in the BRCT domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246124 control chromosomes (gnomAD). c.5527G>C has been reported in the literature in an individual affected with Hereditary Breast and Ovarian Cancer (Sekine_2001). This data does not allow any conclusion about variant significance. Several functional studies have found the variant to be moderately destabilizing in multiple measures such as reduced protein stability, significantly decreased transcriptional activity, and homologous recombination (Lee_2010, Rowling_2010, Gaboriau_2015). A ClinVar submission from another clinical diagnostic laboratory (evaluation after 2014) cites the variant as "likely pathogenic." Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Breast Cancer Information Core |
RCV000112695 | SCV000145567 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 1 | no assertion criteria provided | clinical testing | ||
| Brotman Baty Institute, |
RCV000112695 | SCV001242088 | not provided | Breast-ovarian cancer, familial, susceptibility to, 1 | no assertion provided | in vitro |