Submissions for variant NM_005732.4(RAD50):c.1237C>T (p.Gln413Ter)

gnomAD frequency: 0.00001  dbSNP: rs373428259

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163726	SCV000214300	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-28	criteria provided, single submitter	clinical testing	The p.Q413* pathogenic mutation (also known as c.1237C>T), located in coding exon 8 of the RAD50 gene, results from a C to T substitution at nucleotide position 1237. This changes the amino acid from a glutamine to a stop codon within coding exon 8. 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	RCV000163726	SCV000628137	pathogenic	Hereditary cancer-predisposing syndrome	2023-11-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln413*) 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). This variant is present in population databases (rs373428259, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with RAD50-related conditions. ClinVar contains an entry for this variant (Variation ID: 184469). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194191	SCV001363536	likely pathogenic	Hereditary breast ovarian cancer syndrome	2019-02-14	criteria provided, single submitter	clinical testing	Variant summary: The variant, RAD50 c.1237C>T (p.Gln413X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.1e-06 in 245024 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1237C>T in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002498810	SCV002810219	pathogenic	Nijmegen breakage syndrome-like disorder	2022-04-26	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002498810	SCV004209720	likely pathogenic	Nijmegen breakage syndrome-like disorder	2022-02-02	criteria provided, single submitter	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV003483532	SCV004228891	not provided	Nijmegen breakage syndrome-like disorder; Hereditary cancer-predisposing syndrome		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 02-15-2021 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.