ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.784T>G (p.Leu262Val) (rs149331537)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000116179 SCV000214302 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000116179 SCV000537554 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-29 criteria provided, single submitter clinical testing
Counsyl RCV000206074 SCV000489919 uncertain significance Fanconi anemia, complementation group O 2016-08-10 criteria provided, single submitter clinical testing
Counsyl RCV000411451 SCV000489920 uncertain significance Breast-ovarian cancer, familial 3 2016-08-10 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765378 SCV000896644 uncertain significance Breast-ovarian cancer, familial 3; Fanconi anemia, complementation group O 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000585995 SCV000150088 uncertain significance not provided 2018-05-09 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.784T>G at the cDNA level, p.Leu262Val (L262V) at the protein level, and results in the change of a Leucine to a Valine (TTA>GTA). This variant has been observed in individuals with breast, ovarian, colon, or pancreatic cancer, as well as in at least one control (Thompson 2012, Cunningham 2014, Song 2015, Jonson 2016, Yurgelun 2017). RAD51C Leu262Val was observed at an allele frequency of 0.013% (16/126,684) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the region of interaction with RAD51B, RAD51D, and XRCC3 (Miller 2004). While protein-based in silico analysis supports that this variant does not alter protein structure/function, splice predictors support a deleterious effect. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether RAD51C Leu262Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV000778506 SCV000914779 uncertain significance RAD51C-Related Disorders 2017-09-07 criteria provided, single submitter clinical testing The RAD51C c.784T>G (p.Leu262Val) variant has been reported in three studies and is found in a heterozygous state in five individuals with cancer, all of whom were negative for variants in BRCA1/2 (Thompson et al. 2012; Song et al. 2015; Jonson et al. 2016). Four of the individuals had epithelial ovarian cancer and one male individual had prostate cancer. The p.Leu262Val variant was found in one of 6398 control chromosomes and is reported at a frequency of 0.000126 in the European (non-Finnish) population of the Genome Aggregation Database. Although this variant has not been reported in any individuals with Fanconi anemia, it is known that RAD51C heterozygous variants can also confer carrier status for Fanconi anemia. Based on the evidence, the p.Leu262Val variant is classified as a variant of unknown significance but suspicious for pathogenicity for RAD51C-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000585995 SCV000699825 uncertain significance not provided 2016-12-05 criteria provided, single submitter clinical testing Variant summary: The RAD51C c.784T>G (p.Leu262Val) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). 4/4 splice prediction tools predict that this variant may create/strengthen a cryptical splicing donor site. However, these predictions have yet to be confirmed by functional studies. This variant was found in 8/131698 control chromosomes at a frequency of 0.0000607, which does not exceed the estimated maximal expected allele frequency of a pathogenic RAD51C variant (0.0000625). This variant has also been reported in multiple HBOC patients without clear evidence supporting pathogenicity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS until more information becomes available.
Invitae RCV000206074 SCV000260785 uncertain significance Fanconi anemia, complementation group O 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 262 of the RAD51C protein (p.Leu262Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs149331537, ExAC 0.009%). This variant has been observed  in individuals affected with breast cancer, ovarian cancer, and pancreatic cancer (PMID: 21990120, 26740214, 26261251, 28767289). ClinVar contains an entry for this variant (Variation ID: 128210). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
PreventionGenetics RCV000585995 SCV000807179 uncertain significance not provided 2017-12-05 criteria provided, single submitter clinical testing

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