ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5932G>T (p.Glu1978Ter) (rs587779852)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212035 SCV000149128 pathogenic not provided 2018-05-30 criteria provided, single submitter clinical testing This pathogenic variant is denoted ATM c.5932G>T at the cDNA level and p.Glu1978Ter (E1978X) at the protein level. The substitution creates a nonsense variant, changing a Glutamic Acid to a premature stop codon (GAA>TAA). While this variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay, an RT-PCR assay suggests that this variant may also cause abnormal splicing (Mort 2014). Meta-analyses of breast cancer case-control studies revealed ATM Glu1978Ter is significantly associated with breast cancer (OR=4.7-5.1), suggesting an increased risk that may be higher than for ATM variants in general (Bogdanova 2009, Zhang 2011). Furthermore, Soukupova et al. (2008) demonstrated loss of ATM protein expression in a breast tumor obtained from a known ATM Glu1978Ter carrier, suggesting loss of heterozygosity and supporting pathogenicity of this variant. ATM Glu1978Ter has been reported in several individuals with ataxia-telangiectasia and has been suggested to be a pathogenic founder variant in individuals of Polish and Russian descent (Hacia 1998, Telatar 1998, Teraoka 1999, Laake 2000, Li 2000, Birrell 2005, Mitui 2005). Based on currently available evidence, we consider this variant to be pathogenic. In addition to the association with breast cancer risk, pathogenic variants in ATM may increase the risk of other cancers. An increased risk for colon cancer has been suggested, but the confidence intervals are wide (Thompson 2005, Helgason 2015). An association with pancreatic cancer has also been proposed. A study of 166 unrelated familial pancreatic cancer patients revealed that 2.4% carried an ATM pathogenic variant, and of families with three or more cases of pancreatic cancer, 4.6% carried an ATM pathogenic variant (Roberts 2012). In a subsequent study, Roberts et al. (2016) identified ATM pathogenic variants in approximately 3.4% of familial pancreatic cancer kindreds. Additionally, germline ATM variants have been reported in individuals with aggressive and/or familial prostate cancer (Leongamornlert 2014, Na 2016, Pritchard 2016), as well as familial gastric cancer (Hansford 2015, Huang 2015); however, further studies are needed to determine exact risks. The National Comprehensive Cancer Network has management guidelines for individuals with pathogenic variants in ATM (NCCN). Ataxia telangiectasia (A-T), an autosomal recessive condition, is caused by two pathogenic variants (one affecting each allele) in the ATM gene. This multisystem disorder is characterized by progressive neurodegeneration, telangiectasias, immunodeficiency, and increased cancer risks. If both parents carry an ATM pathogenic variant, the risk to have a child with A-T is 25% for each pregnancy.
Ambry Genetics RCV000115219 SCV000172771 pathogenic Hereditary cancer-predisposing syndrome 2017-04-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000205725 SCV000260557 pathogenic Ataxia-telangiectasia syndrome 2018-12-22 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 1978 (p.Glu1978*) of the ATM gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs587779852, ExAC 0.01%). This variant has been reported in several individuals affected with ataxia-telangiectasia and breast cancer (PMID: 15880721, 16266405, 17124347, 18807267, 19691550, 25614872, 18497957). It has been found to be a prevalent ATM mutation in Eastern Europe (PMID: 15880721, 16266405, 18807267). ClinVar contains an entry for this variant (Variation ID: 127414). Experimental studies indicate that this nonsense change may lead to the out-of-frame skipping of exon 40 (PMID: 10330348, 24451234), although the clinical significance of these findings is unknown. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000205725 SCV000485199 pathogenic Ataxia-telangiectasia syndrome 2016-03-11 criteria provided, single submitter clinical testing
Color RCV000115219 SCV000537636 pathogenic Hereditary cancer-predisposing syndrome 2016-02-09 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515323 SCV000611165 pathogenic Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000205725 SCV000694312 pathogenic Ataxia-telangiectasia syndrome 2017-07-14 criteria provided, single submitter clinical testing Variant summary: The ATM c.5932G>T (p.Glu1978X) variant results in a premature termination codon, predicted to cause a truncated or absent ATM protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., c.7327C>T [p.Arg2443X], c.7517_7520delGAGA [p.Arg2506fsX3], and c.7913G>A [p.Trp2638X]). One in silico tool predicts a damaging outcome for this variant. This variant was found in the control database ExAC and control cohorts reported in the literature at a frequency of 0.0000779 (10/128320 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0039528). The variant has been found in homozygosity and compound heterozygosity in numerous patients and families with ataxia-telangiectasia (Podralska_MGGM_2014; Birrell_HM_2005). Additionally, a large case-control study showed that the variant is enriched in heterozygous breast cancer patients in Eastern European populations (Odds Ratio = 5.6; 95% CI = 1.323.4; p = 0.01; Bogdanova_BCRT_2009). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic for both ataxia-telangiectasia and hereditary cancer. Taken together, this variant is classified as pathogenic.
PreventionGenetics,PreventionGenetics RCV000212035 SCV000805589 pathogenic not provided 2016-03-02 criteria provided, single submitter clinical testing

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