Submissions for variant NM_005732.4(RAD50):c.326_329del (p.Thr109fs)

dbSNP: rs587780155

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000115954	SCV000186501	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-07	criteria provided, single submitter	clinical testing	The c.326_329delCAGA pathogenic mutation, located in coding exon 3 of the RAD50 gene, results from a deletion of 4 nucleotides at nucleotide positions 326 to 329, causing a translational frameshift with a predicted alternate stop codon (p.T109Nfs*20). In one study, this mutation was reported in 6/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439).This mutation has also been reported in multiple individuals with personal and/or family histories of breast, colon, prostate, and other cancers (Foley SB et al. EBioMedicine. 2015 Jan;2:74-81; Schrader KA et al. JAMA Oncol. 2016 Jan;2:104-11; Kotoula V et al. Am J Cancer Res, 2017 Jan;7:98-114; Coppa A et al. Cancer Med. 2018 Jan;7:46-55; Perkins BA et al. Proc. Natl. Acad. Sci. U.S.A. 2018 Apr;115:3686-3691; Carlo MI et al. J Clin Oncol, 2020 02;38:406-414; Akcay IM et al. Int J Cancer, 2021 01;148:285-295). 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.
Invitae	RCV000115954	SCV000548028	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr109Asnfs*20) in the RAD50 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RAD50 are known to be pathogenic (PMID: 19409520). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 26023681). ClinVar contains an entry for this variant (Variation ID: 128017). For these reasons, this variant has been classified as Pathogenic.
GeneKor MSA	RCV000115954	SCV000821770	pathogenic	Hereditary cancer-predisposing syndrome	2021-01-09	criteria provided, single submitter	clinical testing	This variation is a deletion of 4 nucleotides from exon 3 of the RAD50 mRNA, causing a frameshift after codon 109 and the creation of a premature translation stop signal 20 amino acid residues later - p.(Thr109Asnfs*20). This is expected to result in an absent or disrupted protein product. The mutation database ClinVar contains entries for this variant (Variation ID: 128017).
CeGaT Center for Human Genetics Tuebingen	RCV000497298	SCV001154518	uncertain significance	not provided	2022-10-01	criteria provided, single submitter	clinical testing	RAD50: PVS1:Moderate, PM2:Supporting
Baylor Genetics	RCV003467063	SCV004207441	pathogenic	Nijmegen breakage syndrome-like disorder	2022-05-22	criteria provided, single submitter	clinical testing
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001554266	SCV001774871	pathogenic	Breast carcinoma	2021-08-09	no assertion criteria provided	clinical testing