ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1021G>A (p.Val341Ile) (rs200601781)

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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 RCV000167222 SCV000218059 likely benign Hereditary cancer-predisposing syndrome 2017-10-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Subpopulation frequency in support of benign classification,In silico models in agreement (benign)
Color RCV000167222 SCV000903007 likely benign Hereditary cancer-predisposing syndrome 2016-02-26 criteria provided, single submitter clinical testing
Counsyl RCV000234064 SCV000793889 uncertain significance Ataxia-telangiectasia syndrome 2017-09-12 criteria provided, single submitter clinical testing
GeneDx RCV000657017 SCV000292850 uncertain significance not provided 2018-01-05 criteria provided, single submitter clinical testing This variant is denoted ATM c.1021G>A at the cDNA level, p.Val341Ile (V341I) at the protein level, and results in the change of a Valine to an Isoleucine (GTC>ATC). ATM Val341Ile was observed at an allele frequency of 0.013% (2/15292) in individuals of African ancestry in large population cohorts (Lek 2016). ATM Val341Ile was also identified in 1/118 healthy Hispanic 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 Val341Ile is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Val341Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
ITMI RCV000120170 SCV000084312 not provided not specified 2013-09-19 no assertion provided reference population
Invitae RCV000234064 SCV000282857 uncertain significance Ataxia-telangiectasia syndrome 2018-08-13 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 341 of the ATM protein (p.Val341Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs200601781, ExAC 0.02%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 133643). 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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