ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.746G>A (p.Arg249His) (rs730881925)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160916 SCV000211620 uncertain significance not provided 2018-11-20 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.746G>A at the cDNA level, p.Arg249His (R249H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant was observed in at least one individual with breast cancer and one unaffected control subject (Lu 2015, Song 2015). RAD51C Arg249His was not observed at a significant allele frequency in large population cohorts (Lek 2016). RAD51C Arg249His is located in the region of interaction with RAD51B, RAD51D, and XRCC2 (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 Arg249His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000168412 SCV000219106 uncertain significance Fanconi anemia, complementation group O 2019-12-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 249 of the RAD51C protein (p.Arg249His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs730881925, ExAC 0.01%). This variant has been reported in an individual with breast cancer, as well as an unaffected control individual (PMID: 26689913, 26261251). ClinVar contains an entry for this variant (Variation ID: 182828). 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.
Color RCV000234871 SCV000292184 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000234871 SCV000667103 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-30 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Counsyl RCV000663073 SCV000786145 uncertain significance Breast-ovarian cancer, familial 3; Fanconi anemia, complementation group O 2018-03-07 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781789 SCV000920116 uncertain significance not specified 2018-04-23 criteria provided, single submitter clinical testing Variant summary: RAD51C c.746G>A (p.Arg249His) results in a non-conservative amino acid change located in the C-terminal of the Rad51-like DNA recombination and repair protein domain and the RecA-like DNA recombination and repair protein ATP-binding domain. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was observed with an allele frequency of 2e-05 in 255756 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in RAD51C causing Hereditary Breast and Ovarian Cancer (2e-05 vs 6.3e-05), allowing no conclusion about variant significance. The variant, c.746G>A, has been reported in the literature in a cohort of cancer cases (specific phenotype not provided; Lu_2015). This report does not provide an unequivocal conclusion about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as uncertain significance.

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