ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.3407A>G (p.His1136Arg) (rs768490475)

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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 RCV000166838 SCV000217652 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-29 criteria provided, single submitter clinical testing Insufficient evidence
GeneDx RCV000484749 SCV000570830 uncertain significance not provided 2017-06-26 criteria provided, single submitter clinical testing This variant is denoted ATM c.3407A>G at the cDNA level, p.His1136Arg (H1136R) at the protein level, and results in the change of a Histidine to an Arginine (CAT>CGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM His1136Arg was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Histidine and Arginine share similar properties, this is considered a conservative amino acid substitution. ATM His1136Arg occurs at a position that is not conserved and is located in the beta-adaptin interaction domain (Tavtigian 2009). In silico analyses predict that this variant is unlikely to alter protein structure or function. However, splicing models suggest that this variant disrupts the nearby splice acceptor site and may result in aberrant splicing. Based on currently available evidence, it is unclear whether ATM His1136Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000555897 SCV000622419 uncertain significance Ataxia-telangiectasia syndrome 2019-08-04 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 1136 of the ATM protein (p.His1136Arg). The histidine residue is weakly conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs768490475, ExAC no frequency). This variant has been observed in an individual affected with breast cancer (PMID: 28779002). ClinVar contains an entry for this variant (Variation ID: 187143). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Counsyl RCV000555897 SCV000790074 uncertain significance Ataxia-telangiectasia syndrome 2017-03-03 criteria provided, single submitter clinical testing
Mendelics RCV000555897 SCV000838523 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193009 SCV001361528 uncertain significance not specified 2019-04-01 criteria provided, single submitter clinical testing Variant summary: ATM c.3407A>G (p.His1136Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-06 in 276266 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.3407A>G, has been reported in the literature in individuals affected with Chronic Lymphocytic Leukemia (Tiao_2017). This report does not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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