ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.695C>A (p.Ala232Asp)

gnomAD frequency: 0.00004  dbSNP: rs28903089
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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 RCV000164510 SCV000215162 uncertain significance Hereditary cancer-predisposing syndrome 2021-11-01 criteria provided, single submitter clinical testing The p.A232D variant (also known as c.695C>A), located in coding exon 5 of the RAD50 gene, results from a C to A substitution at nucleotide position 695. The alanine at codon 232 is replaced by aspartic acid, an amino acid with dissimilar properties. This alteration was reported in 1/435 UK and 0/46 Finnish familial breast cancer cases (Tommiska J et al. Int. J. Cancer. 2006 Jun;118:2911-6). This alteration was subsequently reported in 1/280 Polish non-selected breast cancer patients and 0/328 controls (Mosor M et al. Breast Cancer Res. Treat. 2010 Sep;123:607-9). This alteration has also been reported as variant of uncertain significance in 1/1197 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 well 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.
Invitae RCV000164510 SCV000254907 uncertain significance Hereditary cancer-predisposing syndrome 2024-01-11 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 232 of the RAD50 protein (p.Ala232Asp). This variant is present in population databases (rs28903089, gnomAD 0.008%). This missense change has been observed in individual(s) with breast cancer (PMID: 16385572, 20571869, 30613976). ClinVar contains an entry for this variant (Variation ID: 185142). 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 not expected to disrupt RAD50 protein function with a negative 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.
GeneKor MSA RCV000164510 SCV000822160 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV003237748 SCV002009642 uncertain significance not provided 2021-11-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002298491 SCV002598824 uncertain significance not specified 2022-09-29 criteria provided, single submitter clinical testing Variant summary: RAD50 c.695C>A (p.Ala232Asp) results in a non-conservative amino acid change located in the Rad50/SbcC-type AAA domain (IPR038729) of 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 4e-05 in 251118 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in RAD50 causing Hereditary Breast And Ovarian Cancer Syndrome (4e-05 vs 6.3e-05), allowing no conclusion about variant significance. c.695C>A has been reported in the literature in individuals affected with breast cancer (e.g. Tommiska_2006, Mosor_2010, Khan_2018, Rizzolo_2019, Tsaousis_2019, Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters have assessed the variant since 2014: all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics RCV003462136 SCV004207392 uncertain significance Nijmegen breakage syndrome-like disorder 2023-06-13 criteria provided, single submitter clinical testing

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