ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4304A>C (p.Lys1435Thr) (rs769980220)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000168111 SCV000218767 uncertain significance Ataxia-telangiectasia syndrome 2019-11-14 criteria provided, single submitter clinical testing This sequence change replaces lysine with threonine at codon 1435 of the ATM protein (p.Lys1435Thr). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and threonine. This variant is present in population databases (rs769980220, ExAC 0.006%). This variant has been observed in several individuals affected with breast cancer (PMID: 28779002). ClinVar contains an entry for this variant (Variation ID: 188194). 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 disruptive, 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.
Ambry Genetics RCV000220668 SCV000273136 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-05 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000478130 SCV000566002 uncertain significance not provided 2018-09-28 criteria provided, single submitter clinical testing This variant is denoted ATM c.4304A>C at the cDNA level, p.Lys1435Thr (K1435T) at the protein level, and results in the change of a Lysine to a Threonine (AAG>ACG). This variant has been observed in breast cancer cases as well as an unaffected control (Decker 2017). ATM Lys1435Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This very is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Lys1435Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000220668 SCV000682193 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-11 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780906 SCV000918545 uncertain significance not specified 2018-05-25 criteria provided, single submitter clinical testing Variant summary: ATM c.4304A>C (p.Lys1435Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 245272 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.4304A>C, has been reported in a publication but is unclear whether it was observed in controls and/or Breast Cancer patients (Decker_2017). This report does 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. Multiple 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.

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