ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.175G>T (p.Ala59Ser) (rs752527112)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214079 SCV000277966 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-24 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000557155 SCV000622279 uncertain significance Ataxia-telangiectasia syndrome 2019-11-04 criteria provided, single submitter clinical testing This sequence change replaces alanine with serine at codon 59 of the ATM protein (p.Ala59Ser). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and serine. This variant is present in population databases (rs752527112, ExAC 0.02%). This variant has not been reported in the literature in individuals with a ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 233566). 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, this variant has uncertain impact on ATM function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000214079 SCV000913528 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-29 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001194331 SCV001363788 uncertain significance not specified 2019-11-01 criteria provided, single submitter clinical testing Variant summary: ATM c.175G>T (p.Ala59Ser) results in a conservative amino acid change located in the Telomere-length maintenance and DNA damage repair (TAN) motif (IPR021668) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 250704 control chromosomes (gnomAD), exclusively reported within the African or African-American subpopulation (3 /16120 alleles). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.175G>T has been reported in the literature in an individual of African ancestry who was affected with Breast Cancer (Tung_2015). This report does not provide unequivocal conclusions about association of the variant with Breast Cancer. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant protein moderately reversed the hyperradiosensitivity phenotype of ATM-null cells, but resulted in increased radiosensitivity compared to ATM wild-type cells, indicating a partial loss of function (Takagi_2017). These data do not allow clear conclusions about the variant significance. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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