ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.1043A>T (p.Asp348Val)

gnomAD frequency: 0.00001  dbSNP: rs111614311
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000218171 SCV000277097 uncertain significance Hereditary cancer-predisposing syndrome 2024-03-29 criteria provided, single submitter clinical testing The p.D348V variant (also known as c.1043A>T), located in coding exon 9 of the RAD51C gene, results from an A to T substitution at nucleotide position 1043. The aspartic acid at codon 348 is replaced by valine, an amino acid with highly dissimilar properties. In multiple assays testing RAD51C function, this alteration showed an abnormal read-out (Hu C et al. Cancer Res, 2023 Aug;83:2557-2571). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.
GeneDx RCV000482149 SCV000565462 uncertain significance not provided 2016-05-23 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.1043A>T at the cDNA level, p.Asp348Val (D348V) at the protein level, and results in the change of an Aspartic Acid to a Valine (GAT>GTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD51C Asp348Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Aspartic Acid and Valine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. RAD51C Asp348Val occurs at a position that is conserved in mammals and is located within the ATPase domain (Kim 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether RAD51C Asp348Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health RCV000218171 SCV000686315 uncertain significance Hereditary cancer-predisposing syndrome 2023-03-15 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with valine at codon 348 of the RAD51C protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RAD51C-related disorders in the literature. This variant has been identified in 3/250000 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV001055557 SCV001219955 uncertain significance Fanconi anemia complementation group O 2024-02-08 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 348 of the RAD51C protein (p.Asp348Val). This variant is present in population databases (rs111614311, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with RAD51C-related conditions. ClinVar contains an entry for this variant (Variation ID: 232848). 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 RAD51C protein function with a positive predictive value of 95%. 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.
Baylor Genetics RCV004567621 SCV005053953 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 3 2024-02-07 criteria provided, single submitter clinical testing

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