Submissions for variant NM_032043.2(BRIP1):c.1717C>G (p.Leu573Val) (rs786202587)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165469	SCV000216200	uncertain significance	Hereditary cancer-predisposing syndrome	2016-03-09	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
GeneDx	RCV000485697	SCV000571022	uncertain significance	not provided	2016-07-18	criteria provided, single submitter	clinical testing	This variant is denoted BRIP1 c.1717C>G at the cDNA level, p.Leu573Val (L573V) at the protein level, and results in the change of a Leucine to a Valine (CTA>GTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRIP1 Leu573Val 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 Leucine and Valine share similar properties, this is considered a conservative amino acid substitution. BRIP1 Leu573Val occurs at a position that is not conserved and is within the Helicase domain (Cantor 2011). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRIP1 Leu573Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000533781	SCV000633568	uncertain significance	Familial cancer of breast; Fanconi anemia, complementation group J	2018-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces leucine with valine at codon 573 of the BRIP1 protein (p.Leu573Val). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a BRIP1-related disease. ClinVar contains an entry for this variant (Variation ID: 185954). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine 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, this variant has uncertain impact on BRIP1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.