ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.671G>A (p.Arg224His) (rs28903088)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000731878 SCV000149872 uncertain significance not provided 2014-02-24 criteria provided, single submitter clinical testing RAD50 has been only recently described in association with cancer predisposition and the risks are not well understood. This variant is denoted RAD50 c.671G>A at the cDNA level, p.Arg224His (R224H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). Tommiska et al. (2006) observed RAD50 Arg224His in one individual with a personal and family history of breast cancer (1/481) and concluded that although it may affect RAD50 function, RAD50 Arg224His is rare, which limits any potential contribution to breast cancer susceptibility even if pathogenic. This variant has also been reported in two case control studies as unknown significance and not associated with breast cancer risk due to a similar frequency in cases and controls (Heikkinen 2003, Heikkinen 2006). RAD50 Arg224His was observed with an allele frequency of 0.1% (8/8600) in European Americans in the NHLBI Exome Sequencing Project. This variant is a conservative substitution of one positive polar amino acid for another, altering a position that is well conserved throughout evolution and is located in the coiled coil domain (Hopfner 2001). Multiple in silico algorithms predict that this variant may be damaging to protein structure and function. On a molecular level, the impact of this missense variant on protein structure and function is not known and thus we consider this to be a variant of uncertain significance. Furthermore, based on the currently available information, cancer risks associated with this variant, and the RAD50 gene, remain unclear.
Ambry Genetics RCV000115963 SCV000172920 benign Hereditary cancer-predisposing syndrome 2015-04-06 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.
Invitae RCV000115963 SCV000253471 likely benign Hereditary cancer-predisposing syndrome 2020-12-01 criteria provided, single submitter clinical testing
Vantari Genetics RCV000115963 SCV000267083 likely benign Hereditary cancer-predisposing syndrome 2015-10-26 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000731878 SCV000859741 uncertain significance not provided 2018-03-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001174561 SCV001337722 likely benign not specified 2020-01-31 criteria provided, single submitter clinical testing Variant summary: RAD50 c.671G>A (p.Arg224His) results in a non-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 damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00072 in 251130 control chromosomes. The observed variant frequency is approximately 11.53 fold of 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 benign. c.671G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer as well as controls (eg. Damiola_2014, Heikkinen_2003, Lhota_2016, Tommiska_2006, Hu_2016, Young_2016). These report(s) do 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, thre classified as benign/likely benign while one classified as VUS. Based on the evidence outlined above, the variant was classified as likely benign.

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