ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.1336A>G (p.Lys446Glu)

gnomAD frequency: 0.00024  dbSNP: rs149217423
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129214 SCV000183964 likely benign Hereditary cancer-predisposing syndrome 2020-11-24 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae RCV000129214 SCV000262130 uncertain significance Hereditary cancer-predisposing syndrome 2024-01-03 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 446 of the RAD50 protein (p.Lys446Glu). This variant is present in population databases (rs149217423, gnomAD 0.05%). This missense change has been observed in individual(s) with breast cancer (PMID: 24894818, 26689913). ClinVar contains an entry for this variant (Variation ID: 140939). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RAD50 protein function with a positive predictive value of 80%. 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.
Fulgent Genetics, Fulgent Genetics RCV000515180 SCV000611510 uncertain significance Nijmegen breakage syndrome-like disorder 2017-05-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780664 SCV000918123 likely benign not specified 2018-10-19 criteria provided, single submitter clinical testing Variant summary: RAD50 c.1336A>G (p.Lys446Glu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00026 in 276328 control chromosomes. The observed variant frequency is approximately 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD50 causing Hereditary Breast and Ovarian Cancer phenotype (6.3e-05), strongly suggesting that the variant is benign. The variant, c.1336A>G, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, without strong evidence for pathogenicity (Damiola_2014, Haiman_2013, Lu_2015, Schoolmeester_2017, Young_2016). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported (RAD51C 5'UTR through exon 5 deletion; Schoolmeester_2017), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Baylor Genetics RCV000515180 SCV004207373 uncertain significance Nijmegen breakage syndrome-like disorder 2023-07-09 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV003477538 SCV004219278 uncertain significance not provided 2023-06-06 criteria provided, single submitter clinical testing In the published literature, this variant has been reported in individuals with breast cancer (PMID: 24894818 (2014)) and ovarian cancer (PMID: 30441849 (2018)). This variant has also been reported in an unaffected individual who also carried a gross exonic deletion in the RAD51C gene (PMID: 28709830 (2017)). The frequency of this variant in the general population, 0.0014 (36/26090 chromosomes in Swedish subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

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