ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.406A>T (p.Met136Leu) (rs587780254)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000571441 SCV000667100 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000571441 SCV000911513 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-29 criteria provided, single submitter clinical testing
GeneDx RCV000116173 SCV000150082 uncertain significance not provided 2017-11-01 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.406A>T at the cDNA level, p.Met136Leu (M136L) at the protein level, and results in the change of a Methionine to a Leucine (ATG>TTG). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in a lung tumor (Seo 2012). RAD51C Met136Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Methionine and Leucine share similar properties, this is considered a conservative amino acid substitution. RAD51C Met136Leu occurs at a position where amino acids with properties similar to Methionine are tolerated across species and is located in the region 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 evidence, it is unclear whether RAD51C Met136Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000205234 SCV000260321 uncertain significance Fanconi anemia, complementation group O 2018-11-08 criteria provided, single submitter clinical testing This sequence change replaces methionine with leucine at codon 136 of the RAD51C protein (p.Met136Leu). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and leucine. This variant is present in population databases (rs587780254, ExAC 0.02%). This variant has not been reported in the literature in individuals with RAD51C-related disease. ClinVar contains an entry for this variant (Variation ID: 128204). 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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