ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5262G>T (p.Lys1754Asn) (rs748900588)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000572138 SCV000660519 uncertain significance Hereditary cancer-predisposing syndrome 2016-06-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000572138 SCV000682258 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-10 criteria provided, single submitter clinical testing
Counsyl RCV000230500 SCV000797236 uncertain significance Ataxia-telangiectasia syndrome 2018-01-18 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763705 SCV000894585 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000482295 SCV000566172 uncertain significance not provided 2019-01-08 criteria provided, single submitter clinical testing This variant is denoted ATM c.5262G>T at the cDNA level, p.Lys1754Asn (K1754N) at the protein level, and results in the change of a Lysine to an Asparagine (AAG>AAT). This variant was observed in individuals with a personal history of breast cancer, as well as an individual with radiation induced choroidal telangiectasia (Decker 2017, Hauke 2018, Mauget-Faysse 2003). This variant was also identified in two siblings with Schimke immuno-osseous dysplasia (SIOD) who were compound heterozygous for two truncating variants in the SMARCAL1 gene known to be associated with this condition (Simon 2014). ATM Lys1754Asn was not observed at a significant allele frequency 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 a deleterious effect. Based on currently available evidence, it is unclear whether ATM Lys1754Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000230500 SCV000282985 uncertain significance Ataxia-telangiectasia syndrome 2018-12-30 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 1754 of the ATM protein (p.Lys1754Asn). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is present in population databases (rs748900588, ExAC 0.004%). This variant has been reported in a heterozygous individual with radiation-induced choroidal telangiectasia (PMID: 12882767). ClinVar contains an entry for this variant (Variation ID: 236734). 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.

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