Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000259337 | SCV000329128 | uncertain significance | not provided | 2016-09-13 | criteria provided, single submitter | clinical testing | This variant is denoted BRCA1 c.4009G>C at the cDNA level, p.Asp1337His (D1337H) at the protein level, and results in the change of an Aspartic Acid to a Histidine (GAC>CAC). Using alternate nomenclature, this variant would be defined as BRCA1 4128G>C. BRCA1 Asp1337His has been observed in at least one individual with a history of breast cancer (Bolognesi 2014). This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Aspartic Acid and Histidine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Asp1337His occurs at a position that is not conserved and is located within the SCD domain and a region known to interact with multiple proteins (Narod 2004, Clark 2012, Chen 1998). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA1 Asp1337His is pathogenic or benign. We consider it to be a variant of uncertain significance. |
Invitae | RCV000637752 | SCV000759227 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2023-11-01 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 1337 of the BRCA1 protein (p.Asp1337His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 25415331, 34178674). ClinVar contains an entry for this variant (Variation ID: 279705). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. 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. |
Ambry Genetics | RCV001021647 | SCV001183292 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-08-22 | criteria provided, single submitter | clinical testing | The p.D1337H variant (also known as c.4009G>C), located in coding exon 9 of the BRCA1 gene, results from a G to C substitution at nucleotide position 4009. The aspartic acid at codon 1337 is replaced by histidine, an amino acid with similar properties. This variant has been previously reported in an individual with a personal history of breast cancer (Bolognesi C et al. PLoS ONE, 2014 Nov;9:e112354) and was reported in an individual within a cohort of 874 unrelated Italian breast or ovarian cancer patients undergoing genetic testing based on suspicion for HBOC (Fanale D. et al. Front Oncol . 2021 Jun;11:682445). 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. |
University of Washington Department of Laboratory Medicine, |
RCV001021647 | SCV003850932 | likely benign | Hereditary cancer-predisposing syndrome | 2023-03-23 | criteria provided, single submitter | curation | Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). |