ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.1875C>G (p.Tyr625Ter)

dbSNP: rs149201802
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000205188 SCV000261499 pathogenic Hereditary cancer-predisposing syndrome 2024-01-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr625*) in the RAD50 gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs149201802, gnomAD 0.06%). This premature translational stop signal has been observed in individual(s) with pancreatic and breast cancer (PMID: 18281469, 25452441). ClinVar contains an entry for this variant (Variation ID: 220719). Studies have shown that this premature translational stop signal results in skipping of exon 12 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000205188 SCV000273485 pathogenic Hereditary cancer-predisposing syndrome 2021-09-30 criteria provided, single submitter clinical testing The p.Y625* pathogenic mutation (also known as c.1875C>G), located in coding exon 12 of the RAD50 gene, results from a C to G substitution at nucleotide position 1875. This changes the amino acid from a tyrosine to a stop codon within coding exon 12. This alteration has been detected in 2/1824 patients with triple-negative breast cancer who were unselected for a family history of breast or ovarian cancer (Couch FJ et al. J Clin Oncol, 2015 Feb;33:304-11). This variant was also reported in 2/1313 early-onset breast cancer cases and 0/1123 population controls (Damiola F et al. Breast Cancer Res, 2014 Jun;16:R58). In addition, this alteration was identified in a 77 year old woman with pancreatic ductal adenocarcinoma and non-Hodgkin's lymphoma and in a male diagnosed with pancreatic cancer (Yurgelun MB et al. Genet Med, 2019 01;21:213-223; Wang X et al. Cancer Res., 2008 Feb;68:971-5). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Counsyl RCV000411352 SCV000489273 pathogenic Nijmegen breakage syndrome-like disorder 2016-09-13 criteria provided, single submitter clinical testing
GeneKor MSA RCV000205188 SCV000821772 pathogenic Hereditary cancer-predisposing syndrome 2020-01-01 criteria provided, single submitter clinical testing This variant is a single amino acid change from Tytosine to a premature translational stop signal at codon 625 of the RAD50 protein. This is expected to result in an absent or disrupted protein product. Truncating variants in RAD50 are known to be pathogenic (PMID: 19409520, 16385572).This variant has been described in the international literature in individuals affected with pancreatic and breast cancer (PMID: 18281469, 25452441) and in individuals undergoing panel testing for hereditary syndrome (PMID: 31159747). The mutation database ClinVar contains entries for this variant (Variation ID: 220719). .
Baylor Genetics RCV000411352 SCV001525046 pathogenic Nijmegen breakage syndrome-like disorder 2024-02-16 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000411352 SCV002019604 pathogenic Nijmegen breakage syndrome-like disorder 2020-08-19 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000411352 SCV002538462 pathogenic Nijmegen breakage syndrome-like disorder 2022-01-13 criteria provided, single submitter curation
Quest Diagnostics Nichols Institute San Juan Capistrano RCV003477703 SCV004219295 pathogenic not provided 2022-11-23 criteria provided, single submitter clinical testing This nonsense variant causes the premature termination of RAD50 protein synthesis. The frequency of this variant in the general population, 0.00056 (20/35426 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 25452441 (2015)) and pancreatic cancer (PMID: 29961768 (2019)). It has also been reported in an individual with personal and/or family history of breast and/or ovarian cancer (PMID:31159747 (2019)). Based on the available information, this variant is classified as pathogenic.
CZECANCA consortium RCV001270999 SCV001451811 pathogenic Breast and/or ovarian cancer 2019-06-11 no assertion criteria provided clinical testing
CZECANCA consortium RCV002280874 SCV002569173 likely pathogenic Hepatocellular carcinoma 2022-05-17 no assertion criteria provided case-control

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