ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.1336A>G (p.Lys446Glu) (rs149217423)

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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 RCV000129214 SCV000183964 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000129214 SCV000262130 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 446 of the RAD50 protein (p.Lys446Glu). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs149217423, ExAC 0.07%). This variant has been reported in individuals affected with breast cancer (PMID: 24894818, 26689913). ClinVar contains an entry for this variant (Variation ID: 140939). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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
Integrated Genetics/Laboratory Corporation of America 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.

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