ClinVar Miner

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

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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 RCV000166722 SCV000217533 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-03 criteria provided, single submitter clinical testing 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
Invitae RCV000541770 SCV000622751 uncertain significance Ataxia-telangiectasia syndrome 2019-12-31 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.
Integrated Genetics/Laboratory Corporation of America RCV001175362 SCV000694352 uncertain significance not specified 2020-07-14 criteria provided, single submitter clinical testing Variant summary: ATM c.7463G>A (p.Cys2488Tyr) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251500 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7463G>A has been reported in the literature in sequencing studies among individuals affected with CLL (Navrkalova_2013, teRaa_2015, Sutton_2015, Spunarova_2019, Tausch_2020; authorship overlap between all of these publications) and sequencing panels for inherited cancers (Susswein_2013), breast cancer and/or ovarian cancer (Lhota_2016 and Lu_2018), and pancreatic cancer (Hu_2018). A co-occurring ATM frameshift variant (c.7878_7882delTTATA, p.A2626fs; not in our database or ClinVar) was reported in at least one IGHV unmutated poorly prognostic CLL patient. These reports do not provide unequivocal conclusions about association of the variant with any of these cancer phenotypes. An overlapping variant that causes the same protein change (c.7463G>T; p.Cys2488Tyr) has been identified in at least one additional HBOC patient (Thorstenson_Can Res_2003). Two publications report experimental evidence evaluating an impact on protein function, however, none of these studies allows convincing conclusions about the variant effect. The variant was reported to not affect protein expression, but diminish autophosphorylation function, though primary evidence was not provided for independent evaluation (Navrkalova_Haem_2013; te Raa_Cell Death Dis_2015). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (uncertain significance, n=4, likely pathogenic, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000255700 SCV001148443 likely pathogenic not provided 2018-10-01 criteria provided, single submitter clinical testing
Color RCV000166722 SCV001359120 uncertain significance Hereditary cancer-predisposing syndrome 2020-04-07 criteria provided, single submitter clinical testing
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.

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