ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5633C>T (p.Ser1878Leu) (rs758908522)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489997 SCV000577000 uncertain significance not provided 2018-07-09 criteria provided, single submitter clinical testing The S1878L variant has not been published previously in association with ataxia-telangiectasia to our knowledge. It has been observed as part of a study on ATM-associated familial breast cancer; however, the authors did not specify whether it was observed in the case or control population (Nguyen-Dumont et al., 2009). It has also been observed in the control population of a separate study on breast cancer (Tavtigian et al., 2009). The variant is observed in 1/16438 (0.018%) alleles from individuals of South Asian background in the ExAC dataset, including one homozygote (Lek et al., 2016). S1878L is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000546553 SCV000622608 uncertain significance Ataxia-telangiectasia syndrome 2018-12-22 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 1878 of the ATM protein (p.Ser1878Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs758908522, ExAC 0.02%). This variant has been reported in the literature in control individuals not affected with an ATM-related disease (PMID: 19781682). ClinVar contains an entry for this variant (Variation ID: 426534). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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 RCV000569421 SCV000667861 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000569421 SCV000687631 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-10 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780900 SCV000918536 uncertain significance not specified 2018-04-06 criteria provided, single submitter clinical testing Variant summary: ATM c.5633C>T (p.Ser1878Leu) results in a non-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 3.7e-05 in 243456 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not higher than expected for a pathogenic variant in ATM causing Breast Cancer (3.7e-05 vs 0.001), allowing no conclusion about variant significance. c.5633C>T has been reported in the literature in individuals affected with Breast Cancer and CLL. These reports do not provide unequivocal conclusions about an association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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