ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.3836G>A (p.Arg1279His)

gnomAD frequency: 0.00007  dbSNP: rs375710541
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129203 SCV000183947 uncertain significance Hereditary cancer-predisposing syndrome 2023-09-29 criteria provided, single submitter clinical testing The p.R1279H variant (also known as c.3836G>A), located in coding exon 25 of the RAD50 gene, results from a G to A substitution at nucleotide position 3836. The arginine at codon 1279 is replaced by histidine, an amino acid with highly similar properties. This alteration was identified in multiple individuals diagnosed with breast and/or ovarian cancer (Damiola F et al. Breast Cancer Res, 2014 Jun;16:R58; Kim H et al. Breast Cancer Res Treat, 2017 01;161:95-102; Nunziato M et al. Front Med (Lausanne), 2022 Aug;9:894358). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV000129203 SCV000289069 uncertain significance Hereditary cancer-predisposing syndrome 2023-11-10 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1279 of the RAD50 protein (p.Arg1279His). This variant is present in population databases (rs375710541, gnomAD 0.01%). This missense change has been observed in individual(s) with a personal and/or family history of breast cancer (PMID: 24894818, 27783279). ClinVar contains an entry for this variant (Variation ID: 140931). 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.
Fulgent Genetics, Fulgent Genetics RCV000765811 SCV000897201 uncertain significance Nijmegen breakage syndrome-like disorder 2018-10-31 criteria provided, single submitter clinical testing

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