ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.687del (p.Ser229fs) (rs760146707)

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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 RCV000164362 SCV000214996 pathogenic Hereditary cancer-predisposing syndrome 2018-03-28 criteria provided, single submitter clinical testing The c.687delT pathogenic mutation, located in coding exon 5 of the RAD50 gene, results from a deletion of one nucleotide at nucleotide position 687, causing a translational frameshift with a predicted alternate stop codon (p.S229Rfs*6). This alteration was first reported in 2/151 Finnish familial breast/ovarian cancer individuals as well as in 6/1000 cancer free controls (Heikkinen K, J. Med. Genet. 2003 Dec; 40(12):e131). In a case control study of 317 consecutive newly diagnosed Finnish breast cancer patients and 1000 geographically matched healthy controls, eight breast cancer patients and six controls were carriers (95% CI 1.5–12.5, P = 0.008). Haplotype analysis suggests this is a Finnish founder mutation (Heikkinen K, Carcinogenesis 2006 Aug; 27(8):1). 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 RCV000409900 SCV000488545 likely pathogenic Nijmegen breakage syndrome-like disorder 2016-06-13 criteria provided, single submitter clinical testing
Invitae RCV000164362 SCV000628316 pathogenic Hereditary cancer-predisposing syndrome 2020-10-05 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 5 of the RAD50 mRNA (c.687delT), causing a frameshift at codon 229. This creates a premature translational stop signal (p.Ser229Argfs*6) and is expected to result in an absent or disrupted protein product. This variant has been described as a Finnish founder mutation, and has been reported in many individuals and families affected with hereditary breast and ovarian cancer in that population (PMID: 14684699, 16385572, 16474176, 25452441). In a small case-control study involving 371 cases and 1,000 controls from the Northern Finnish population, this variant was reported to confer an increased risk for breast cancer (OR 4.3, 95% CI: 1.5-12.5, P=0.008) (PMID: 16474176, 19092773). However, this has not been further established in a larger study or meta-analysis. Experimental studies have shown that while this variant produces a transcript that is not subject to nonsense-mediated decay (PMID: 14684699), lymphoblastoid cell lines derived from carriers of this variant exhibit no expression of the mutant protein (PMID: 16385572). Additionally, carriers of this variant have been shown to have an increase in genomic instability (PMID: 16474176). For these reasons, this variant has been classified as Pathogenic.

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