Submissions for variant NM_005732.4(RAD50):c.3902A>G (p.Lys1301Arg)

gnomAD frequency: 0.00001  dbSNP: rs201766077

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132370	SCV000187460	likely benign	Hereditary cancer-predisposing syndrome	2023-02-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000132370	SCV000254902	benign	Hereditary cancer-predisposing syndrome	2024-01-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001582609	SCV001821440	likely benign	not specified	2023-08-08	criteria provided, single submitter	clinical testing	Variant summary: RAD50 c.3902A>G (p.Lys1301Arg) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.7e-05 in 253702 control chromosomes, predominantly at a frequency of 0.0006 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 10 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD50 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.3902A>G has been reported in the literature in individuals affected with breast cancer, colorectal cancer, or multiple colorectal polyps (examples: Damiola_2014, Li_2018, Wang_2019, Yao_2022, Hernandez_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. One co-occurrence with another pathogenic variant has been reported (BRCA2 c.6096dupT, p.Ile2033fs; Wang_2019), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28102005, 24894818, 34716202, 29891727, 30982232, 22216297, 35186721, 26787654). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=2; Likely benign, n=1; Benign, n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Sema4, Sema4	RCV002258813	SCV002538522	uncertain significance	Nijmegen breakage syndrome-like disorder	2021-06-23	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV002258813	SCV003813685	uncertain significance	Nijmegen breakage syndrome-like disorder	2020-04-03	criteria provided, single submitter	clinical testing
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153431	SCV003843447	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing