ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.692A>G (p.His231Arg) (rs587782229)

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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 RCV000130924 SCV000185836 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000130924 SCV000682377 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-10 criteria provided, single submitter clinical testing
Counsyl RCV000457349 SCV000789627 uncertain significance Ataxia-telangiectasia syndrome 2017-02-08 criteria provided, single submitter clinical testing
GeneDx RCV000423648 SCV000512134 uncertain significance not provided 2017-06-27 criteria provided, single submitter clinical testing This variant is denoted ATM c.692A>G at the cDNA level, p.His231Arg (H231R) at the protein level, and results in the change of a Histidine to an Arginine (CAT>CGT). This variant was reported in an individual with ataxia telangiectasia; however, a second ATM variant was not found in this patient (Magliozzi 2006). ATM His231Arg was also observed in at least one family with a cancer history that was suggestive for hereditary breast and ovarian cancer (Thorstenson 2003, Tavtigian 2009). ATM His231Arg 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 His231Arg occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether ATM His231Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000457349 SCV000547151 uncertain significance Ataxia-telangiectasia syndrome 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 231 of the ATM protein (p.His231Arg). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in one individual with ataxia-talengiectasia, however, a second variant was not reported (PMID: 17124347). This variant has also been reported in an individual with breast cancer (PMID: 19781682), and an individual from a breast and ovarian cancer family, although it is unclear if this individual is affected (PMID: 12810666). ClinVar contains an entry for this variant (Variation ID: 142096). 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 RCV000457349 SCV000838475 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing

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