Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000590234 | SCV000699112 | uncertain significance | not provided | 2016-10-03 | criteria provided, single submitter | clinical testing | Variant summary: The BRCA1 c.4169A>G (p.Asp1390Gly) variant causes a missense change involving a non-conserved nucleotide with 2/4 in silico tools (SNPs&Go not captured here due to low reliability index) predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest has not been observed in controls (ExAC, 1000 Gs, or ESP), nor has it been, to our knowledge reported in affected individuals via publications and/or reputable clinical diagnostic laboratories/databases. An internal LCA sample reports the variant to co-occur with a likely pathogenic BRCA2 variant, c.718_719delCT (p.L240fsX4 - classified as likely pathogenic). Because of the absence of clinical information and the lack of functional studies, the variant has been classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available. |
| Invitae | RCV000637634 | SCV000759101 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2019-09-26 | criteria provided, single submitter | clinical testing | Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15". The glycine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. This variant has been observed in an individual with breast cancer (Invitae). However, in that individual, a pathogenic allele was also identified in BRCA2, which suggests that this c.4169A>G variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 496377). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with glycine at codon 1390 of the BRCA1 protein (p.Asp1390Gly). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and glycine. |