ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2771G>A (p.Arg924Gln) (rs587782298)

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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 RCV000131181 SCV000186128 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-28 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000465123 SCV000547012 uncertain significance Ataxia-telangiectasia syndrome 2019-10-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 924 of the ATM protein (p.Arg924Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs587782298, ExAC 0.06%). This variant has been observed in individuals affected with breast cancer, and healthy controls (PMID: 19781682, 30287823). ClinVar contains an entry for this variant (Variation ID: 142194). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.
GeneDx RCV000483446 SCV000564621 uncertain significance not provided 2018-07-11 criteria provided, single submitter clinical testing This variant is denoted ATM c.2771G>A at the cDNA level, p.Arg924Gln (R924Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant was observed in 1/4112 breast cancer cases and 0/2399 controls in a large meta-analysis (Tavtigian 2009). ATM Arg924Gln was observed at an allele frequency of 0.04% (12/30782) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Arg924Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000131181 SCV000682076 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-12 criteria provided, single submitter clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030524 SCV001193472 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Integrated Genetics/Laboratory Corporation of America RCV001193037 SCV001361582 uncertain significance not specified 2019-02-27 criteria provided, single submitter clinical testing Variant summary: The variant, ATM c.2771G>A (p.Arg924Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 298486 control chromosomes (gnomAD, Momozawa_2018, Tavtigian_2009). This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.00014 vs 0.001), allowing no conclusion about variant significance. The variant c.2771G>A has been reported in the literature in individuals affected with Breast Cancer (Momozawa_2018, Tavtigian_2009). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Pediatrics, Samsung Medical Center, Samsung Medical Center RCV001252852 SCV001163995 uncertain significance Microcephaly no assertion criteria provided research

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