ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.2397G>C (p.Gln799His) (rs61749630)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212916 SCV000149849 uncertain significance not provided 2013-11-06 criteria provided, single submitter clinical testing RAD50, which is involved in DNA damage repair as part of the Fanconi Anemia pathway, has been only recently described in association with cancer predisposition and the risks are not well understood This variant is denoted RAD50 c.2397G>C at the cDNA level, p.Gln799His (Q799H) at the protein level, and results in the change of a Glutamine to a Histidine (CAG>CAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD50 Gln799His was not observed at significant allele frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a semi-conservative substitution of a neutral polar amino acid for a positive polar one, altering a position that is well conserved throughout evolution and is located in the a coiled coil domain, a known structural motif, per UniProt. In silico analyses are inconsistent with regard to the effect this variant may have on 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 RCV000115940 SCV000183958 likely benign Hereditary cancer-predisposing syndrome 2018-10-30 criteria provided, single submitter clinical testing Last nucleotide of exon;Insufficient or conflicting evidence;RNA Studies;No disease association in small case-control study;In silico models in agreement (benign)
Invitae RCV000115940 SCV000261275 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-06 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 799 of the RAD50 protein (p.Gln799His). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and histidine. This variant also falls at the last nucleotide of exon 14 of the RAD50 coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs61749630, ExAC 0.1%). This variant has been reported in individuals affected with breast and stomach cancer. However, in one of these individuals a pathogenic allele was also identified in RAD50, which suggests that this c.2397G>C variant was not the primary cause of disease (PMID: 25452441, 24894818, 26689913, Invitae). ClinVar contains an entry for this variant (Variation ID: 128004). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098), but according to multiple splice site algorithms this particular variant is not predicted to significantly affect splicing. These predictions have not been confirmed by published functional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000662916 SCV000785859 uncertain significance Nijmegen breakage syndrome-like disorder 2017-12-19 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000662916 SCV000895677 uncertain significance Nijmegen breakage syndrome-like disorder 2018-10-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000212916 SCV001154519 uncertain significance not provided 2017-04-01 criteria provided, single submitter clinical testing

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