ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.4561G>C (p.Val1521Leu)

gnomAD frequency: 0.00001  dbSNP: rs141329176
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219002 SCV000273233 uncertain significance Hereditary cancer-predisposing syndrome 2022-04-20 criteria provided, single submitter clinical testing The p.V1521L variant (also known as c.4561G>C), located in coding exon 29 of the ATM gene, results from a G to C substitution at nucleotide position 4561. The valine at codon 1521 is replaced by leucine, an amino acid with highly similar properties. In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). Additionally, this alteration was seen in 0/732 breast cancer patients, 1/189 colorectal cancer patients and 1/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 01;148:285-295).This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000657107 SCV000293794 uncertain significance not provided 2024-11-12 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Identified in individuals with breast, renal, or colorectal cancer and also in cancer-free control(s) (PMID: 26689913, 29684080, 32658311, 33471991); This variant is associated with the following publications: (PMID: 26094954, 26689913, 29684080, 32658311, 33471991)
Labcorp Genetics (formerly Invitae), Labcorp RCV000467522 SCV000546703 uncertain significance Ataxia-telangiectasia syndrome 2024-01-30 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1521 of the ATM protein (p.Val1521Leu). This variant is present in population databases (rs141329176, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 229874). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Genetic Services Laboratory, University of Chicago RCV000235643 SCV000593512 uncertain significance not specified 2017-05-05 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000219002 SCV001733808 uncertain significance Hereditary cancer-predisposing syndrome 2021-11-16 criteria provided, single submitter clinical testing This missense variant replaces valine with leucine at codon 1521 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. In a large international case-control study, this variant was reported in 2/60464 breast cancer cases and 0/53461 controls (PMID: 33471991). This variant has been identified in 2/251366 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Baylor Genetics RCV003468986 SCV004211999 uncertain significance Familial cancer of breast 2024-03-14 criteria provided, single submitter clinical testing
Natera, Inc. RCV000467522 SCV002084837 uncertain significance Ataxia-telangiectasia syndrome 2021-05-24 no assertion criteria provided clinical testing

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