Submissions for variant NM_000051.4(ATM):c.2250G>A (p.Lys750=)

gnomAD frequency: 0.00003  dbSNP: rs1137887

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235101	SCV000149058	pathogenic	not provided	2022-06-21	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); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 24549055, 17968022, 18321536, 12497634, 17910737, 19691550, 10980530, 23612382, 11889466, 28779002, 21665257, 26681312, 9463314, 16941484, 25614872, 21445571, 9887333, 17203191, 23454770, 18164969, 23632773, 25037873, 26845104, 8789452, 12552559, 12815592, 17124347, 24763289, 10425038, 28152038, 27671921, 26270727, 29101607, 29785153, 27779110, 29600275, 10330348, 31159747, 31843900, 31948886, 26896183, 32885271, 32427313, 27535533, 32918381)
Invitae	RCV000003185	SCV000166090	pathogenic	Ataxia-telangiectasia syndrome	2024-01-30	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. This variant also falls at the last nucleotide of exon 14, which is part of the consensus splice site for this exon. This variant is present in population databases (rs1137887, gnomAD 0.008%). This variant has been observed in individuals with ataxia-telangiectasia (PMID: 9463314, 9887333, 10330348, 10980530, 19691550). ClinVar contains an entry for this variant (Variation ID: 3044). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in multiple RNA products (Invitae). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000115149	SCV000183940	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-01	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). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. 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 Diagnostics, LLC DBA Color Health	RCV000115149	SCV000682042	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-14	criteria provided, single submitter	clinical testing	This synonymous variant does not change the encoded amino acid at codon 750 of the ATM protein, but it causes a G to A substitution at the last nucleotide of exon 14 of the ATM gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. RNA studies using carrier-derived RNA have shown that this variant causes the skipping of exon 14 (also known as exon 16 in the literature)(PMID: 9887333, 18321536, 31843900). The aberrant transcript is predicted to result in an in-frame deletion of 42 amino acids of the ATM protein. This variant has been reported in the homozygous state or compound heterozygous state with an additional pathogenic ATM variant in many individuals affected with ataxia-telangiectasia (PMID: 10330348, 10980530, 12552559, 17124347, 18321536, 18634022, 19691550, 21792198, 25614872, 27671921, 35145552; DOI: 10.1055/s-0041-1739584). This variant has also been reported in individuals affected with breast cancer (PMID: 21445571, 26681312, 28779002, 29785153). 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 (clinicalgenome.org). 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	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 Center for Human Genetics Tuebingen	RCV000235101	SCV001747026	likely pathogenic	not provided	2024-03-01	criteria provided, single submitter	clinical testing	ATM: PM2, PS3:Moderate, PS4:Moderate
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; http://gnomad.broadinstitute.org). 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).
Sema4, Sema4	RCV000115149	SCV002536436	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-03	criteria provided, single submitter	curation
3billion	RCV000003185	SCV002572759	pathogenic	Ataxia-telangiectasia syndrome	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). Synonymous variant leading to alternate splicing. Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 10330348 , 10980530 , 9463314 , 9887333). In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.94). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 10330348 , 10980530 , 19691550 , 9463314 , 9887333). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000003044 / PMID: 26681312). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	RCV000003185	SCV002574829	likely pathogenic	Ataxia-telangiectasia syndrome	2022-09-22	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000003185	SCV002764786	pathogenic	Ataxia-telangiectasia syndrome	2020-09-02	criteria provided, single submitter	clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000003185	SCV003924410	pathogenic	Ataxia-telangiectasia syndrome		criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000235101	SCV004026020	pathogenic	not provided	2022-04-28	criteria provided, single submitter	clinical testing	PS4, PP3, PM2_SUP, PS3
Baylor Genetics	RCV001171385	SCV004207528	pathogenic	Familial cancer of breast	2024-01-26	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235101	SCV004220083	pathogenic	not provided	2018-04-25	criteria provided, single submitter	clinical testing	This variant has been reported in patients with breast or ovarian cancer (PMIDs: 21445571 (2011), 24549055 (2014), 26845104 (2016), 32427313 (2020), 33280026 (2021)) and Ataxia-Telangiectasia (PMIDs: 10980530 (2000), 11889466 (2002), and 12552559 (2003)). Peer-reviewed experiments also report aberrant splicing observed in RNA extracted from patient samples and a lack of apparent protein expression (PMIDs: 9887333 (1999) and 10330348 (1999)). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper ATM mRNA splicing . Based on the available information, this variant is classified as pathogenic.
Myriad Genetics, Inc.	RCV001171385	SCV004931251	pathogenic	Familial cancer of breast	2024-01-17	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9463314, 10330348].
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.
BRCAlab, Lund University	RCV001171385	SCV002588800	likely pathogenic	Familial cancer of breast	2022-08-26	no assertion criteria provided	clinical testing