Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000478611 | SCV000567041 | uncertain significance | not provided | 2015-06-24 | criteria provided, single submitter | clinical testing | This variant is denoted BRCA2 c.505A>G at the cDNA level, p.Lys169Glu (K169E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAG>GAG). Using alternate nomenclature, this variant would be defined as BRCA2 733A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Lys169Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Lysine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Lys169Glu occurs at a position where amino acids with properties similar to Lysine are tolerated across species and is not located in a known functional domain (Roy 2012). 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 BRCA2 Lys169Glu is pathogenic or benign. We consider it to be a variant of uncertain significance. |
| Labcorp Genetics |
RCV001212806 | SCV001384403 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2019-08-31 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 419318). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 sequence change replaces lysine with glutamic acid at codon 169 of the BRCA2 protein (p.Lys169Glu). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamic acid. |