ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.869T>C (p.Ile290Thr) (rs749645694)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000575382 SCV000674688 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000575382 SCV000909735 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-19 criteria provided, single submitter clinical testing
GeneDx RCV000236194 SCV000293729 uncertain significance not provided 2015-12-22 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.869T>C at the cDNA level, p.Ile290Thr (I290T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). This variant has been reported in at least one family with breast cancer (Romero 2011, Osorio 2012). RAD51C Ile290Thr 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 Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. RAD51C Ile290Thr occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species and is located in the ATPase domain (Kim 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether RAD51C Ile290Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000524726 SCV000650027 uncertain significance Fanconi anemia, complementation group O 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 290 of the RAD51C protein (p.Ile290Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs749645694, ExAC 0.01%). This variant has been reported in a family affected with breast cancer (PMID: 21537932). ClinVar contains an entry for this variant (Variation ID: 246254). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.

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