ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.280A>C (p.Ile94Leu) (rs28903085)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000857578 SCV000149857 likely benign not provided 2020-11-06 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 24093751, 20981092, 14684699, 27884173, 27153395, 23555315, 26483394, 16385572, 27782108, 28492532, 28202063, 26209080)
Ambry Genetics RCV000115948 SCV000172767 benign Hereditary cancer-predisposing syndrome 2014-11-20 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: 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.
Genetic Services Laboratory, University of Chicago RCV000193160 SCV000248649 likely benign not specified 2015-12-11 criteria provided, single submitter clinical testing
Invitae RCV000115948 SCV000262389 benign Hereditary cancer-predisposing syndrome 2020-12-04 criteria provided, single submitter clinical testing
Counsyl RCV000410963 SCV000488743 likely benign Nijmegen breakage syndrome-like disorder 2016-09-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000193160 SCV000698652 benign not specified 2020-08-31 criteria provided, single submitter clinical testing Variant summary: RAD50 c.280A>C (p.Ile94Leu) results in a conservative amino acid change located in the Rad50/SbcC-type AAA domain of 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 0.0034 in 255166 control chromosomes, predominantly at a frequency of 0.0061 within the South Asian subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 98-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 South Asian origin. Further evidence in support of a benign polymorphism is provided by a recent study in Arabic individuals (a population underrepresented in publicly available databases) reporting the variant as benign based on a population frequency of >1% and its presence in the homozygous state in multiple individuals who lack the reported phenotype (Abouelhoda_2016). c.280A>C has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Heikkinen_2003, Tommiska_2006, Young_2018) but was also reported in controls (e.g. Heikkinen_2003, Kurki_2014). In addition, one family with breast cancer history was documented with one unaffected and two affected sisters carrying the variant (Jalkh_2017). These data do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and one ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000410963 SCV000745438 likely benign Nijmegen breakage syndrome-like disorder 2016-06-15 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000410963 SCV000745944 likely benign Nijmegen breakage syndrome-like disorder 2017-04-25 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000857578 SCV001154517 uncertain significance not provided 2017-05-01 criteria provided, single submitter clinical testing

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