ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8495G>A (p.Arg2832His) (rs529296539)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000159755 SCV000215582 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000159755 SCV000292186 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-06 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764951 SCV000896123 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000656764 SCV000209772 uncertain significance not provided 2018-12-10 criteria provided, single submitter clinical testing This variant is denoted ATM c.8495G>A at the cDNA level, p.Arg2832His (R2832H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). ATM Arg2832His has been reported in individuals with breast, lung, and pancreatic cancer (Lu 2015, Decker 2017, Chaffee 2018). This variant was also identified in 1/98 healthy Central 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 Arg2832His was observed at an allele frequency of 0.05% (16/30,774) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is located within the kinase domain (Stracker 2013). 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 Arg2832His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
ITMI RCV000120163 SCV000084305 not provided not specified 2013-09-19 no assertion provided reference population
Invitae RCV000462707 SCV000546694 uncertain significance Ataxia-telangiectasia syndrome 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 2832 of the ATM protein (p.Arg2832His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs529296539, ExAC 0.08%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 133638). 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. A different missense substitution at this codon (p.Arg2832Cys) has been reported to be pathogenic (PMID: 9443866, 10817650, 10873394, 18634022, 12552559). This suggests that the arginine residue is critical for ATM protein function and that other missense substitutions at this position may also be pathogenic. 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 RCV000462707 SCV000838616 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing

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