ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.520A>G (p.Thr174Ala) (rs864622278)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000205015 SCV000259955 uncertain significance Fanconi anemia, complementation group O 2019-10-16 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 174 of the RAD51C protein (p.Thr174Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a RAD51C-related disease. ClinVar contains an entry for this variant (Variation ID: 219853). 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, this variant has uncertain impact on RAD51C function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000486898 SCV000567745 uncertain significance not provided 2017-08-21 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.520A>G at the cDNA level, p.Thr174Ala (T174A) at the protein level, and results in the change of a Threonine to an Alanine (ACT>GCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD51C Thr174Ala was not observed in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). Since Threonine and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. RAD51C Thr174Ala occurs at a position that is not conserved and is located in the regions of interaction with RAD51B, RAD51D, and XRCC3 (Miller 2004). 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 RAD51C Thr174Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000570805 SCV000671923 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-02 criteria provided, single submitter clinical testing Insufficient evidence
Counsyl RCV000663210 SCV000786394 uncertain significance Breast-ovarian cancer, familial 3; Fanconi anemia, complementation group O 2018-04-24 criteria provided, single submitter clinical testing

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