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

dbSNP: rs149201802

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	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	2019-01-07	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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