ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.3253A>G (p.Ile1085Val)

gnomAD frequency: 0.00111  dbSNP: rs143189763
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235202 SCV000149862 uncertain significance not provided 2023-01-24 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); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with colorectal cancer (Dharwadkar et al., 2020); This variant is associated with the following publications: (PMID: 23555315, 33359728)
Ambry Genetics RCV000115953 SCV000185694 likely benign Hereditary cancer-predisposing syndrome 2018-07-20 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 RCV000115953 SCV000253466 benign Hereditary cancer-predisposing syndrome 2024-01-19 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781784 SCV000920110 benign not specified 2018-05-18 criteria provided, single submitter clinical testing Variant summary: RAD50 c.3253A>G (p.Ile1085Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The observed variant frequency within African control individuals in the gnomAD database is approximately 50 fold above the estimated maximal expected allele frequency for a pathogenic variant in RAD50 causing Hereditary Breast and Ovarian Cancer phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. c.3253A>G has been reported in the literature but does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting interpretations including VUS (1x), likely benign (1x), and benign (1x). Based on the evidence outlined above, the variant was classified as benign.
Sema4, Sema4 RCV002257409 SCV002538499 likely benign Nijmegen breakage syndrome-like disorder 2021-05-26 criteria provided, single submitter curation
Revvity Omics, Revvity RCV002257409 SCV003813687 uncertain significance Nijmegen breakage syndrome-like disorder 2022-06-22 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235202 SCV004220099 likely benign not provided 2023-03-30 criteria provided, single submitter clinical testing

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