ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.397C>A (p.Gln133Lys) (rs387907159)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000217976 SCV000278408 uncertain significance Hereditary cancer-predisposing syndrome 2016-07-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000236579 SCV000293947 uncertain significance not provided 2018-07-02 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.397C>A at the cDNA level, p.Gln133Lys (Q133K) at the protein level, and results in the change of a Glutamine to a Lysine (CAA>AAA). This variant has been identified in at least one individual with ovarian cancer and in one individual with breast cancer (Cunningham 2014, Song 2015, Hauke 2018). RAD51C Gln133Lys was not observed in large population cohorts (Lek 2016). This variant is located in the region of interaction with RAD51B, RAD51D and XRCC3 (Miller 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether RAD51C Gln133Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000648257 SCV000770071 uncertain significance Fanconi anemia, complementation group O 2017-08-09 criteria provided, single submitter clinical testing This sequence change replaces glutamine with lysine at codon 133 of the RAD51C protein (p.Gln133Lys). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with ovarian cancer (PMID: 26261251). ClinVar contains an entry for this variant (Variation ID: 233936). 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 disruptive, 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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