ClinVar Miner

Submissions for variant NM_005591.3(MRE11):c.19C>T (p.Leu7Phe) (rs73517551)

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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 RCV000129361 SCV000184125 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000524527 SCV000254861 uncertain significance Ataxia-telangiectasia-like disorder 2018-10-09 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 7 of the MRE11 protein (p.Leu7Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs73517551, ExAC 0.1%). This variant has not been reported in the literature in individuals with MRE11-related disease. ClinVar contains an entry for this variant (Variation ID: 141030). 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.
Integrated Genetics/Laboratory Corporation of America RCV000780431 SCV000917677 likely benign not specified 2017-10-12 criteria provided, single submitter clinical testing Variant summary: The MRE11A c.19C>T (p.Leu7Phe) variant involves the alteration of a conserved nucleotide not located in any known domain. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 42/277216 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.001665 (40/24028). This frequency is about 27 times the estimated maximal expected allele frequency of a pathogenic MRE11A variant causing HBOC (0.0000625), but only slightly higher than that of a pathogenic MRE11A variant causing Ataxia-telangiectasia-like disorder (0.0013156). In addition, this variant has been reported in 10/2559 African American individuals older than age 70 years who have never had cancer. Although multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance, this variant is classified as likely benign based on its relatively high frequency in African American healthy individuals.

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