ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2250G>A (p.Lys750=) (rs1137887)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235101 SCV000149058 pathogenic not provided 2021-07-01 criteria provided, single submitter clinical testing Published functional studies demonstrate that the variant causes skipping of exon 14, also known as exon 16 using alternate nomenclature, and reduces ATM protein expression levels (Sandoval et al., 1999; Teraoka et al., 1999; Prodosmo et al., 2013; Shirts et al., 2016; Casadei et al., 2019); In silico analysis supports a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27535533, 31948886, 29101607, 16941484, 25614872, 21445571, 24549055, 23454770, 19691550, 10980530, 26845104, 8789452, 12552559, 27671921, 29785153, 29600275, 9887333, 10330348, 31843900, 31159747, 26681312, 21665257, 27779110, 28779002, 26270727, 28152038, 10425038, 24763289, 17124347, 23612382, 11889466, 12815592, 25037873, 23632773, 17910737, 17203191, 18164969, 18321536, 12497634, 17968022, 9463314)
Invitae RCV000003185 SCV000166090 pathogenic Ataxia-telangiectasia syndrome 2020-10-19 criteria provided, single submitter clinical testing This sequence change affects codon 750 of the ATM mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ATM protein. It also falls at the last nucleotide of exon 14 of the ATM coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs1137887, ExAC 0.002%). This variant has been observed in individuals and families affected with ataxia-telangiectasia (PMID: 9463314, 10980530, 9887333, 10330348, 19691550). Exon 14 is also referred to as exon 16 in the literature. ClinVar contains an entry for this variant (Variation ID: 3044). Experimental studies evaluating the splicing effect of this variant reported that it resulted in skipping of exon 14 (c.2125_2250del, p.Ile709_Lys750del) from the ATM mRNA (PMID: 9887333, 10330348). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000115149 SCV000183940 pathogenic Hereditary cancer-predisposing syndrome 2020-01-28 criteria provided, single submitter clinical testing ​The c.2250G>A pathogenic mutation (also known as p.K750K), located in coding exon 13 of the ATM gene, results from a G to A substitution at nucleotide position 2250. This nucleotide substitution does not change the lysine at codon 750; however, it occurs at the last base pair of coding exon 13. This mutation has been reported in several patients with ataxia-telangiectasia (A-T) (Laake K et al. Hum. Mutat. 2000 Sep;16:232-46; Stankovic T et al. Am. J. Hum. Genet. 1998 Feb;62:334-45; Sandoval N et al. Hum. Mol. Genet. 1999 Jan;8:69-79). This mutation has been reported to cause skipping of coding exon 13 (also referred to as exon 16 in the literature), resulting in the in-frame deletion of 42 amino acids (Laake K et al. Hum. Mutat. 2000 Sep;16:232-46; Stankovic T et al. Am. J. Hum. Genet. 1998 Feb;62:334-45; Sandoval N et al. Hum. Mol. Genet. 1999 Jan;8:69-79). RNA studies have demonstrated that this alteration results in the same splicing event reported in the literature (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
University of Washington Department of Laboratory Medicine, University of Washington RCV000003185 SCV000266148 pathogenic Ataxia-telangiectasia syndrome 2017-07-11 criteria provided, single submitter clinical testing
Counsyl RCV000003185 SCV000486402 pathogenic Ataxia-telangiectasia syndrome 2016-05-27 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115149 SCV000682042 pathogenic Hereditary cancer-predisposing syndrome 2020-10-12 criteria provided, single submitter clinical testing This synonymous variant does not change the amino acid sequence of the ATM protein. However, this variant alters the conserved c.G at the last nucleotide position of exon 14 and is predicted to disrupt RNA splicing. Functional RNA studies have shown that this variant causes the in-frame skipping of exon 14 (p.Glu709_Lys750del) (PMID: 9887333, 18321536, 31843900). This variant has been reported in individuals affected with breast cancer (PMID: 21445571, 26681312) and in over ten individuals affected with ataxia-telangiectasia (PMID: 10330348, 10980530, 12552559, 17124347, 18321536, 18634022, 19691550, 21792198, 25614872, 27671921). This variant has been identified in 11/250736 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease ( Based on the available evidence, this variant is classified as Pathogenic.
GeneKor MSA RCV000115149 SCV000821696 likely pathogenic Hereditary cancer-predisposing syndrome 2020-01-01 criteria provided, single submitter clinical testing This variant occurs at the last base of exon 14, a position that is highly conserved in the human and other genomes. Although it does not result in an amino acid substitution, it has been demonstrated to affect splicing of the mRNA, specifically in frame skipping of the entire exon 14 (c.2125_2250del, p.(Ile709_Lys750del) (PMID: 10330348). This variant is listed in population databases at a very low frequency (rs1137887, ExAC <0.01%) and has been described in the international bibliography in individuals and families affected with Ataxia Telangiectasia (A-T) (PMID: 19691550, 10980530, 10330348 ). The mutation database ClinVar contains entries for this variant (Variation ID:3044).
Athena Diagnostics Inc RCV000235101 SCV000840925 pathogenic not provided 2018-04-25 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000762817 SCV000893175 pathogenic Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-10-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000003185 SCV000918520 pathogenic Ataxia-telangiectasia syndrome 2018-03-23 criteria provided, single submitter clinical testing Variant summary: ATM c.2250G>A (p.Lys750Lys) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predict the variant abolishes a 5' splicing donor site and three predict the variant weakens a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing. The variant allele was found at a frequency of 4.5e-05 in 245598 control chromosomes. This frequency is not higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (4.5e-05 vs 0.004), allowing no conclusion about variant significance. c.2250G>A has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia. These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All labs classified it as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000115149 SCV001448882 pathogenic Hereditary cancer-predisposing syndrome 2019-03-20 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000235101 SCV001480133 pathogenic not provided 2021-02-01 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000235101 SCV001747026 pathogenic not provided 2021-05-01 criteria provided, single submitter clinical testing
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group RCV000115149 SCV001911500 pathogenic Hereditary cancer-predisposing syndrome 2020-06-17 criteria provided, single submitter clinical testing The c.2250G>A variant has an allele frequency of 0.0047%, (11/236,200 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.0078%, (8/102,444 alleles) in the European (non-Finnish) subpopulation subpopulation (no population frequency criterion met; This variant in the last nucleotide of the exon leads to a splicing alteration as per SPiCE predictor (PP3). Two independent assays with ataxia telangiectasia patients’ mRNA showed the skipping of exon 14 (r.2125_2250del), which will produce an in-frame deletion of 42 amino acids (p.Ile709_Lys750del) (PMID: 10330348, 9887333). It has been reported in at least eighteen ataxia-telangiectasia probands in homozygosis or together with (likely) pathogenic variants, which awards 4 points to this variant as per ClinGen SVI Recommendation for in trans Criterion (PM3_VeryStrong; PMID: 16941484, 25037873, 25614872, 21792198, 19691550, 10873394, 29600275, 10330348, 9463314, 27671921, 9887333, 12552559, 17124347). Moreover, lymphoblastoid cell lines of patients carrying this variant have been reported to have residual or absent ATM protein expression, no kinase activity on 6 substrates and increased chromosome instability (PS3_Moderate; PMID: 9887333, 10330348, 27613453, 21792198, 29600275). Although this variant is located in a non-highly conserved nucleotide based on its PhyloP score (BP7), it meets criteria to be classified as pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PP3 + PS3_Moderate + PM3_VeryStrong + BP7 (PMID: 33280026).
OMIM RCV000003185 SCV000023343 pathogenic Ataxia-telangiectasia syndrome 2002-04-01 no assertion criteria provided literature only
King Laboratory,University of Washington RCV001171385 SCV001251283 pathogenic Familial cancer of breast 2019-09-01 no assertion criteria provided research
Natera, Inc. RCV000003185 SCV001461023 pathogenic Ataxia-telangiectasia syndrome 2020-09-16 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354985 SCV001549729 likely pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Lys750= variant was identified in 12 of 886 proband chromosomes (frequency: 0.01) from individuals or families with Ataxia Telangiectasia or breast cancer (Chessa 2009, Goidescu 2017, Laake 2000, Podralska 2014, Sandoval 1999, Stankovic 1998). The variant was also identified in dbSNP (ID: rs1137887) as "With Pathogenic allele", ClinVar (classified as likely pathogenic by Color, GeneDx and GeneKor MSA; and as pathogenic by Invitae, Ambry Genetics and four other submitters), and in LOVD 3.0 (16x). The variant was identified in control databases in 11 of 245598 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 5464 chromosomes (freq: 0.0002), Latino in 1 of 33512 chromosomes (freq: 0.00003), and European in 9 of 111430 chromosomes (freq: 0.00008), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Lys750= variant is not predicted to result in a change of amino acid; however, it occurs in the invariant region of the splice consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. In addition, multiple studies have demonstrated this variant affects splicing of the mRNA, leading to exon skipping and a predicted in-frame deletion of 42 residues from Glu709 to Lys750 (Sandoval 1999, Teraoka 1999). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.

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