Submissions for variant NM_005732.4(RAD50):c.2165dup (p.Glu723fs)

dbSNP: rs397507178

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129381	SCV000184147	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-13	criteria provided, single submitter	clinical testing	The c.2165dupA pathogenic mutation, located in coding exon 13 of the RAD50 gene, results from a duplication of A at nucleotide position 2165, causing a translational frameshift with a predicted alternate stop codon (p.E723Gfs*5). This alteration has been reported multiple individuals diagnosed with breast or prostate cancer (Lin PH et al. Oncotarget. 2016 Feb;7:8310-20; Fan C et al. Int J Cancer, 2018 10;143:1935-1942; Goidescu IG et al. Clujul Med, 2018 Apr;91:157-165; Wang YA et al. BMC Cancer, 2018 03;18:315; Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This alteration was also identified in trans with c.3109_3111del in an individual with bone marrow failure, microcephaly, skin pigmentation, nail dysplasia, dental loss and dysmorphia (Chansel-Da Cruz M et al. Cell Rep, 2020 12;33:108559). Of note, this alteration is also known as c.2157dupA in published literature. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000129381	SCV000255302	pathogenic	Hereditary cancer-predisposing syndrome	2025-02-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu723Glyfs*5) 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: 25452441, 26824983). This variant is also known as c.2157dupA. ClinVar contains an entry for this variant (Variation ID: 141045). For these reasons, this variant has been classified as Pathogenic.
Genetic Services Laboratory, University of Chicago	RCV000500926	SCV000596683	pathogenic	Nijmegen breakage syndrome-like disorder	2016-04-20	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000708625	SCV000821773	pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing	This variant is a duplication of 1 nucleotide in exon 13 of RAD50 mRNA (c.2165dupA). causing a frameshift at codon 723. This creates a premature translational stop signal (p.Glu723Glyfs*5) and is expected to result in an absent or disrupted protein product. Truncating mutations in RAD50 are known to be pathogenic. The mutation database ClinVar contains an entry for this variant (Variation ID: 37377/).
Revvity Omics, Revvity	RCV000500926	SCV002019624	pathogenic	Nijmegen breakage syndrome-like disorder	2023-04-21	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000500926	SCV002538471	pathogenic	Nijmegen breakage syndrome-like disorder	2021-10-13	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV000500926	SCV002810892	pathogenic	Nijmegen breakage syndrome-like disorder	2024-04-26	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000500926	SCV003799166	pathogenic	Nijmegen breakage syndrome-like disorder	2022-10-03	criteria provided, single submitter	clinical testing	PVS1, PS3, PM2
Baylor Genetics	RCV000500926	SCV004207341	pathogenic	Nijmegen breakage syndrome-like disorder	2024-03-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000708625	SCV004219302	pathogenic	not provided	2021-11-19	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00042 (8/19162 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast or ovarian cancer (PMIDs: 31742824 (2020), 26824983 (2016), and 25452441 (2015)). Based on the available information, this variant is classified as pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000500926	SCV004809890	pathogenic	Nijmegen breakage syndrome-like disorder	2024-04-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000708625	SCV005325699	uncertain significance	not provided	2023-01-03	criteria provided, single submitter	clinical testing	Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); Frameshift variant predicted to result in protein truncation and nonsense mediated decay in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; Observed in individuals with breast and/or ovarian cancer (Couch et al., 2015; Lin et al., 2016; Lilyquist et al., 2017; Goidescu et al., 2018); This variant is associated with the following publications: (PMID: 32832836, 26824983, 30755392, 31159747, 26689913, 33378670, 35768433, 34803902, 34680501, 29739316, 35595529, 29566657, 31742824, 33804961, 29726012, 32295079, 25452441, 16385572, 29785153, 28888541)
CZECANCA consortium	RCV001271000	SCV001451812	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	case-control