ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6095G>A (p.Arg2032Lys) (rs139770721)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000159742 SCV000214152 pathogenic Hereditary cancer-predisposing syndrome 2018-02-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Functionally-validated splicing mutation,Last nucleotide of exon,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Blueprint Genetics RCV000212037 SCV000928203 pathogenic not provided 2019-02-05 criteria provided, single submitter clinical testing
Color RCV000159742 SCV000682303 pathogenic Hereditary cancer-predisposing syndrome 2015-09-08 criteria provided, single submitter clinical testing
Counsyl RCV000167946 SCV000220988 likely pathogenic Ataxia-telangiectasia syndrome 2014-12-23 criteria provided, single submitter literature only
Fulgent Genetics,Fulgent Genetics RCV000762824 SCV000893182 pathogenic Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000212037 SCV000209757 pathogenic not provided 2018-10-02 criteria provided, single submitter clinical testing This variant is denoted ATM c.6095G>A at the cDNA level. Located in the last nucleotide of its exon, splicing models predict ATM c.6095G>A to result in loss of the adjacent splice donor site, and Western blot studies have revealed exonic skipping (Telatar 1998, Teraoka 1999). Although the nucleotide substitution results in the change of an Arginine to a Lysine at codon 2032, and this variant also is called Arg2032Lys in the literature, we are using only the nucleotide nomenclature to refer to the variant since the defect is determined to be one of splicing rather than the resulting missense change. This variant has been reported individuals with pancreatic and familial breast/ovarian cancer, and has been observed in the compound heterozygous state with a second pathogenic ATM variant in several individuals with Ataxia-telangiectasia (Sandoval 1999, Thorstenson 2003, Roberts 2012, Podralska 2014). ATM c.6095G>A was not observed at a significant allele frequency in large population cohorts (Lek 2016). The nucleotide which is altered, a Guanine (G) at base 6095, is conserved across species. Based on the current evidence, we consider this variant to be pathogenic.
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000709711 SCV000839886 pathogenic Familial cancer of breast 2018-01-30 criteria provided, single submitter clinical testing This c.6095G>A (p.R2032K) variant in the ATM gene has been reported in multiple Ataxia-telangiectasia (AT) patients with significantly higher prevalence [PMID: 10980530, 15390180,16266405] than that observed as extremely low in general population according to gnomad database. This variant, in trans with other deleterious variants, has been reported in AT patients [PMID: 27159176, 25614872]. Functional studies showed that this mutant causes abnormal splicing and loss of expression of ATM proteins [PMID: 9887333, 10330348]. Multiple in silico predictions suggest this arginine to lysine is deleterious, while the c.6095G>A change might affect the splicing of messenger RNA as the last nucleotide on exon 41. Based upon above evidences, this c.6095G>A (p.R2032K) variant in the ATM gene is classified as pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000167946 SCV000694316 pathogenic Ataxia-telangiectasia syndrome 2015-12-07 criteria provided, single submitter clinical testing
Invitae RCV000167946 SCV000218594 pathogenic Ataxia-telangiectasia syndrome 2019-01-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 2032 of the ATM protein (p.Arg2032Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and lysine. It also falls at the last nucleotide of exon 41 of the ATM coding sequence. This variant is present in population databases (rs139770721, ExAC 0.008%). This variant has been reported as compound heterozygous or homozygous in individuals affected with ataxia-telangiectasia (PMID: 9887333, 16266405, 10330348, 25614872, 10980530, 27159176). It has also been reported in individuals affected with pancreatic cancer (PMID: 22585167) and gastric cancer (PMID: 26506520). ClinVar contains an entry for this variant (Variation ID: 181974). Experimental studies have shown that this missense change causes skipping of exon 41 (called exon 43) in lymphocytes derived from an affected individual (PMID: 9887333). Skipping of exon 41 is predicted to lead to a frameshift and premature translational stop signal at codon 2007, resulting in an absent or disrupted protein product (PMID: 10330348). For these reasons, this variant has been classified as Pathogenic.

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