ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7463G>A (p.Cys2488Tyr) (rs774281788)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166722 SCV000217533 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000255700 SCV000322033 likely pathogenic not provided 2018-03-16 criteria provided, single submitter clinical testing This variant is denoted ATM c.7463G>A at the cDNA level, p.Cys2488Tyr (C2488Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGT>TAT). ATM Cys2488Tyr was observed in the germline of a patient with chronic lymphocytic leukemia, and subsequent analyses revealed a positive ATM protein level, though defective protein function (Navrkalova 2013). The same amino acid change, ATM Cys2488Tyr, due to a different nucleotide substitution, ATM c.7463G>T, has been observed in at least one individual with breast and/or ovarian cancer (Thorstenson 2003, Tavtigian 2009). Another non-conservative ATM variant at the same residue, ATM Cys2488Arg, has both been shown to impact ATM protein expression, phosphorylation in response to ionizing radiation, and nuclear localization (Jacquemin 2012). ATM Cys2488Tyr was not observed at a significant frequency in large population cohorts (Lek 2016, NHLBI Exome Sequencing Project). Since Cysteine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Cys2488Tyr occurs at a position that is conserved through mammals and is located within the FAT domain (Stracker 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available information, we consider ATM Cys2488Tyr to be a likely pathogenic variant
GenomeConnect, ClinGen RCV000509266 SCV000607208 not provided Ataxia-telangiectasia syndrome; Hereditary cancer no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Integrated Genetics/Laboratory Corporation of America RCV000255700 SCV000694352 uncertain significance not provided 2017-06-05 criteria provided, single submitter clinical testing Variant summary: The ATM c.7463G>A (p.Cys2488Tyr) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution in the Armadillo-type fold and PIK-related kinase domains (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in the large control database ExAC at a frequency of 0.0000164 (2/121582 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). The variant has been identified in at least one HBOC patient (Lhota_Clin Genet_2016) as well as several chronic lympocytic leukemia (CLL) patients (Sutton_Haem_2014; Navrkalova_Haem_2013; te Raa_Cell Death Dis_2015), without strong evidence for pathogenicity in any case. Functional studies assessing the variant have been performed that suggest the variant does not affect protein expression, but does diminish autophosphorylation function, though evidence was not provided for independent evaluation (Navrkalova_Haem_2013; te Raa_Cell Death Dis_2015). An overlapping variant that causes the same protein change (c.7463G>T; p.Cys2488Tyr) has been identified in at least 1 additional HBOC patient (Thorstenson_Can Res_2003). Multiple clinical diagnostic laboratories/reputable databases have classified this variant with conflicting interpretations, including uncertain significance and likely pathogenic. Taken together, this variant is classified as VUS.
Invitae RCV000541770 SCV000622751 uncertain significance Ataxia-telangiectasia syndrome 2019-01-11 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 2488 of the ATM protein (p.Cys2488Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is present in population databases (rs774281788, ExAC 0.003%). This variant has been reported in individuals with breast cancer and chronic lymphocytic leukemia (PMID: 26681312, 23585524). ClinVar contains an entry for this variant (Variation ID: 187037). Experimental studies have reported that this missense change disrupts protein function (PMID: 23585524). 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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