ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.695C>A (p.Ala232Asp) (rs28903089)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164510 SCV000215162 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneKor MSA RCV000164510 SCV000822160 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Invitae RCV000164510 SCV000254907 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-24 criteria provided, single submitter clinical testing This sequence change replaces alanine with aspartic acid at codon 232 of the RAD50 protein (p.Ala232Asp). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and aspartic acid. This variant is present in population databases (rs28903089, ExAC 0.02%). This variant has been reported in the literature in individuals affected with breast cancer (PMID: 20571869, 16385572). This variant has also been observed in an individual with endometrial hyperplasia and colon polyps (Invitae). However, in that individual a pathogenic allele was identified in RAD50, which suggests that this c.695C>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 185142). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The aspartic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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