ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.730A>G (p.Ile244Val) (rs199886026)

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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 RCV000160915 SCV000217706 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000160915 SCV000686381 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-22 criteria provided, single submitter clinical testing
GeneDx RCV000587417 SCV000211619 uncertain significance not provided 2018-10-23 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.730A>G at the cDNA level, p.Ile244Val (I244V) at the protein level, and results in the change of an Isoleucine to a Valine (ATT>GTT). RAD51C Ile244Val was reported in an individual with breast cancer and in an individual with an early-onset mismatch repair proficient sigmoid tumor (Tung 2015, Pearlman 2017). Additionally, this variant was not identified in 2808 individuals with a personal and/or family history of ovarian cancer, but was detected in 1/2312 controls (Loveday 2012). RAD51C Ile244Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the region of interaction with RAD51B, RAD51D, and XRCC3 (Miller 2004). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether RAD51C Ile244Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587417 SCV000699820 uncertain significance not provided 2016-08-01 criteria provided, single submitter clinical testing Variant summary: The RAD51C c.730A>G (p.Ile244Val) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a benign outcome. This variant was found in 6/123714 control chromosomes at a frequency of 0.0000485, which does not exceed the estimated maximal expected allele frequency of a pathogenic RAD51C variant (0.0000625). The variant has been reported in the literature as absent in an ovarian cancer cohort but was found once in controls (Loveday_2012). Multiple clinical diagnostic laboratories/reputable databases classified this variant as a VUS. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000206770 SCV000261221 uncertain significance Fanconi anemia, complementation group O 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 244 of the RAD51C protein (p.Ile244Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with RAD51C-related disease. ClinVar contains an entry for this variant (Variation ID: 182827). 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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