ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1444A>C (p.Lys482Gln) (rs202173660)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115142 SCV000172911 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Athena Diagnostics Inc RCV000211962 SCV000840917 uncertain significance not provided 2018-04-05 criteria provided, single submitter clinical testing
Color RCV000115142 SCV000537540 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-18 criteria provided, single submitter clinical testing
Counsyl RCV000197378 SCV000800380 uncertain significance Ataxia-telangiectasia syndrome 2018-06-01 criteria provided, single submitter clinical testing
GeneDx RCV000211962 SCV000149051 uncertain significance not provided 2018-09-06 criteria provided, single submitter clinical testing This variant is denoted ATM c.1444A>C at the cDNA level, p.Lys482Gln (K482Q) at the protein level, and results in the change of a Lysine to a Glutamine (AAA>CAA). This variant has been observed in individuals with breast cancer and colon cancer, but was also present in healthy control populations (Tung 2015, Decker 2017, Tiao 2017, Yurgelun 2017, Cock-Rada 2018, Hauke 2018). ATM Lys482Gln was observed at an allele frequency of 0.02% (22/111630) in individuals of European ancestry in large population cohorts (Lek 2016). ATM Lys482Gln is not located in a known functional domain. In silico analysis, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether ATM Lys482Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GeneKor MSA RCV000115142 SCV000821831 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779759 SCV000916535 uncertain significance not specified 2017-09-28 criteria provided, single submitter clinical testing Variant summary: The ATM c.1444A>C (p.Lys482Gln) variant causes a missense change involving the alteration of a conserved nucleotide. 3/3 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). The variant was found in the control population dataset of gnomAD in 25/246152 control chromosomes at a frequency of 0.0001016, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). This variant was found in HBOC, CRC, and Mllerian adenosarcoma patients without strong evidence for causality (Cock-Rada_2017, Yurgelun_2017, Howitt_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS, until more definitive clinical and functional studies become available.
Invitae RCV000197378 SCV000254060 uncertain significance Ataxia-telangiectasia syndrome 2018-01-20 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamine at codon 482 of the ATM protein (p.Lys482Gln). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamine. This variant is present in population databases (rs202173660, ExAC 0.01%). This variant has been reported in an individual with a personal or family history of breast and/or ovarian cancer (PMID: 28528518). ClinVar contains an entry for this variant (Variation ID: 127338). 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.
Mendelics RCV000197378 SCV000838488 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing

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