ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4724G>A (p.Arg1575His) (rs550552791)

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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 RCV000159727 SCV000215125 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000159727 SCV000537529 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-14 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000587149 SCV000705520 uncertain significance not provided 2017-02-17 criteria provided, single submitter clinical testing
GeneDx RCV000587149 SCV000209740 uncertain significance not provided 2018-11-27 criteria provided, single submitter clinical testing This variant is denoted ATM c.4724G>A at the cDNA level, p.Arg1575His (R1575H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant was reported to co-occur with ATM Ala2274Thr in individuals with breast cancer, chronic lymphocytic leukemia, and multiple myeloma (Austen 2008, Tavtigian 2009, Navrkalova 2013) and was also reported to occur independently in a pediatric patient with medulloblastoma and in at least one unaffected control (Skowronska 2012, Zhang 2015). Functional studies interrogating ATM Arg1575His demonstrated kinase activity similar to wild type (Austen 2008, Barone 2009). ATM Arg1575His was observed at an allele frequency of 0.01% (16/126332) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Arg1575His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587149 SCV000694290 uncertain significance not provided 2016-04-25 criteria provided, single submitter clinical testing Variant summary: The c.4724G>A variant affects a conserved nucleotide, resulting in amino acid change from Arg to His. 4/4 in-silico tools predict damaging outcome for this variant. This variant is found in 13/126060 control chromosomes including the broad and large populations of ExAC at an allele frequency of 0.000103, which does not exceed the maximal expected frequency of a pathogenic allele (0.0039528) in this gene. No homozygotes have been reported in general population. The variant has been reported in three patients in literature (Austen_2008, Tavtigian_2008, and Navrkalova_2012) -- one with breast cancer, second with multiple myeloma and the third with chronic lymphocytic leukemia (CLL), without strong evidence for causality. In two leukemic patients, it was reported as a germline variant and the patients also carried p.Ala2274Thr with no proven phase information. In the CLL patient somatic variant p.Gln984Glu variant as well as a large deletion (11q-) was detected. In vitro functional study revealed no alteration in kinase activity (Austen_2008). Although available lines of data may suggests for a possible benign outcome, the variants role in causation of primary phenotype, A-T, needs to be further clarified. Three clinical laboratories in ClinVar classify the variant to have uncertain significance. Taken together, this variant has currently been classified as a Variant of Unknown Significance.
Invitae RCV000204984 SCV000261090 uncertain significance Ataxia-telangiectasia syndrome 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1575 of the ATM protein (p.Arg1575His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs550552791, ExAC 0.02%). This variant has been reported in the literature in individuals with breast cancer and chronic lymphocytic leukemia (PMID: 19781682, 23585524), as well as in an unaffected individual (PMID: 21933854). ClinVar contains an entry for this variant (Variation ID: 181960). Experimental studies have shown that this missense change does not affect ATM stability or kinase activity (PMID: 19431188, 18573109). 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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