ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7351G>C (p.Ala2451Pro) (rs587779862)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115247 SCV000149156 uncertain significance not provided 2014-02-19 criteria provided, single submitter clinical testing An ATM variant displaying apparent mosaicism was detected, meaning the variant was detected in some, but not all, cells. This variant is denoted ATM c.7351G>C at the cDNA level, p.Ala2451Pro (A2451P) at the protein level, and results in the change of an Alanine to a Proline (GCC>CCC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Ala2451Pro was not observed 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 amino acid substitution, altering a position that is well conserved throughout evolution and is located in the FAT domain (UniProt). Multiple in silico algorithms predict that this variant may be damaging to protein structure and function. Based on the currently available information, we consider ATM Ala2451Pro to be a variant of uncertain significance. This variant appears to be mosaic, as the variant allele was present but underrepresented in comparison to the normal allele. This result was confirmed using alternate, non-overlapping primers, making it unlikely that this result is due to uneven DNA amplification. Therefore, this variant is interpreted to be present in some, but not all, cells in this peripheral blood specimen. Neither Sanger nor Next Generation sequencing is a quantitative test; thus, it is not possible to determine more precisely the level of mosaicism in this specimen. Moreover, the level of mosaicism may be different in other tissues. As somatic mosaicism generally results from a post-zygotic event, parents and siblings are not likely at risk to carry this mosaic variant. Germline mosaicism and transmission to the offspring of this patient, however, cannot be excluded.
Invitae RCV000707200 SCV000836287 uncertain significance Ataxia-telangiectasia syndrome 2018-06-18 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 2451 of the ATM protein (p.Ala2451Pro). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and proline. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 127441). 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"). 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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