ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.412A>C (p.Asn138His) (rs141690729)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000760062 SCV000149723 uncertain significance not provided 2018-08-17 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.412A>C at the cDNA level, p.Asn138His (N138H) at the protein level, and results in the change of an Asparagine to a Histidine (AAT>CAT). This variant has been observed in at least one individual with ovarian cancer (Konstanta 2018). RAD51D Asn138His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the RAD51C binding domain (Miller 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether RAD51D Asn138His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000572128 SCV000674693 uncertain significance Hereditary cancer-predisposing syndrome 2020-06-02 criteria provided, single submitter clinical testing The p.N138H variant (also known as c.412A>C), located in coding exon 5 of the RAD51D gene, results from an A to C substitution at nucleotide position 412. The asparagine at codon 138 is replaced by histidine, an amino acid with similar properties. This alteration has been reported in an ovarian cancer patient from a Greek breast and/or ovarian cancer cohort (Konstanta I et al. J. Hum. Genet., 2018 Nov;63:1149-1158). It has also been reported as a variant of unknown significance in 5/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color RCV000572128 SCV000686451 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-24 criteria provided, single submitter clinical testing
Invitae RCV000649680 SCV000771512 uncertain significance Breast-ovarian cancer, familial 4 2019-11-08 criteria provided, single submitter clinical testing This sequence change replaces asparagine with histidine at codon 138 of the RAD51D protein (p.Asn138His). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and histidine. This variant is present in population databases (rs141690729, ExAC 0.004%). This variant has been observed in an individual affected with ovarian cancer (PMID: 30111881). ClinVar contains an entry for this variant (Variation ID: 127888). 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: "Possibly 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.
GeneKor MSA RCV000572128 SCV000822178 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000760062 SCV000889821 uncertain significance not provided 2019-08-10 criteria provided, single submitter clinical testing

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