ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.6095G>A (p.Arg2032Lys) (rs139770721)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Ambry Genetics RCV000159742 SCV000214152 pathogenic Hereditary cancer-predisposing syndrome 2019-09-04 criteria provided, single submitter clinical testing <span style="background-color:initial">The c.6095G>A<span style="background-color:initial"> pathogenic mutation (also known as p.R2032K), located in coding exon 40 of the ATM gene, results from a G to A substitution at nucleotide position 6095. The amino acid change results in arginine to lysine at codon 2032, an amino acid with highly similar properties. This alteration has been described as a founder mutation in the Polish population and has been detected in conjunction with a second mutation in numerous probands with ataxia-telangiectasia (A-T) (Li A and Swift M. Am. J. Med. Genet<span style="background-color:initial">. 2000 May;92:170-7; Mitui M et al. Ann. Hum. Genet.<span style="background-color:initial"> 2005 Nov;69(Pt 6):657-64. Podralska MJ et al. Mol Genet Genomic Med. 2014 Nov;2:504-11; Beier R et al. Bone Marrow Transplant. 2016 09;51:1271-4<span style="background-color:initial">). This mutation has also been reported in high-risk breast cancer cohorts (Schubert S et al. Int. J. Cancer 2018 Nov; Podralska M et al. Mol Genet Genomic Med 2014 Nov;2(6):504-11). This change occurs in the highly-conserved last base pair of coding exon 40, which makes it likely to have some effect on normal mRNA splicing. RT-PCR analysis performed on RNA isolated from an A-T individual with this alteration was reported to result in exon skipping (Sandoval N et al. Hum. Mol. Genet.<span style="background-color:initial"> 1999 Jan;8:69-79). RNA studies have shown the same abnormal splicing event reported in the literature (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000167946 SCV000218594 pathogenic Ataxia-telangiectasia syndrome 2020-10-21 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. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. 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). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with the skipping of exon 41 (called exon 43), which introduces a frameshift (PMID: 9887333). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000167946 SCV000220988 likely pathogenic Ataxia-telangiectasia syndrome 2014-12-23 criteria provided, single submitter literature only
Color Health, Inc RCV000159742 SCV000682303 pathogenic Hereditary cancer-predisposing syndrome 2015-09-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000167946 SCV000694316 pathogenic Ataxia-telangiectasia syndrome 2015-12-07 criteria provided, single submitter clinical testing
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.
Fulgent Genetics,Fulgent Genetics RCV000762824 SCV000893182 pathogenic Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-10-31 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000212037 SCV000928203 pathogenic not provided 2019-02-05 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000709711 SCV001367968 pathogenic Familial cancer of breast 2019-05-20 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PM3,PP3.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV000709711 SCV001499611 likely pathogenic Familial cancer of breast 2020-04-02 criteria provided, single submitter clinical testing
GeneReviews RCV000167946 SCV000328292 pathogenic Ataxia-telangiectasia syndrome 2016-10-27 no assertion criteria provided literature only
CZECANCA consortium RCV001391204 SCV001593147 pathogenic Carcinoma of pancreas 2021-03-04 no assertion criteria provided case-control

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