ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.659C>T (p.Ala220Val) (rs145355104)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000159677 SCV000216941 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
CeGaT Praxis fuer Humangenetik Tuebingen RCV000513410 SCV000608614 uncertain significance not provided 2017-03-31 criteria provided, single submitter clinical testing
Color RCV000159677 SCV000682355 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-27 criteria provided, single submitter clinical testing
Counsyl RCV000527646 SCV000796083 uncertain significance Ataxia-telangiectasia syndrome 2017-12-07 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764936 SCV000896108 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000120165 SCV000209678 uncertain significance not specified 2015-07-18 criteria provided, single submitter clinical testing This variant is denoted ATM c.659C>T at the cDNA level, p.Ala220Val (A220V) at the protein level, and results in the change of an Alanine to a Valine (GCG>GTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Ala220Val was identified in 1/62 healthy East Asian individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. ATM Ala220Val was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. ATM Ala220Val occurs at a position that is not conserved across species, with Valine as the native residue in a few species, and is not located in a known functional domain (Tavtigian 20009, Stracker 2013). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether ATM Ala220Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
ITMI RCV000120165 SCV000084307 not provided not specified 2013-09-19 no assertion provided reference population
Invitae RCV000527646 SCV000622681 uncertain significance Ataxia-telangiectasia syndrome 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 220 of the ATM protein (p.Ala220Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs145355104, ExAC 0.04%). This variant has not been reported in the literature in individuals with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 133640). 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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