ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2125C>G (p.Leu709Val) (rs80358489)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164754 SCV000215428 likely benign Hereditary cancer-predisposing syndrome 2018-02-28 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign)
GeneDx RCV000236275 SCV000293480 uncertain significance not provided 2018-01-30 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.2125C>G at the cDNA level, p.Leu709Val (L709V) at the protein level, and results in the change of a Leucine to a Valine (CTG>GTG). This variant, previously published as BRCA2 2353C>G, has been observed in at least two individuals with a personal or family history of breast and/or ovarian cancer (Velasco 2005, Infante 2006). BRCA2 Leu709Val 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. BRCA2 Leu709Val occurs at a position that is not conserved and is located in the region of interaction with NPM1 (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Leu709Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Health, Inc RCV000164754 SCV000688744 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-23 criteria provided, single submitter clinical testing
Invitae RCV001297703 SCV001486732 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-10-07 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 709 of the BRCA2 protein (p.Leu709Val). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs80358489, ExAC 0.003%). This variant has been reported in an individual and a family affected with breast and/or ovarian cancer (PMID: 15937982, 16758124). ClinVar contains an entry for this variant (Variation ID: 51247). 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, 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.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113018 SCV000146009 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing

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