rs1137887

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_000051.4(ATM):c.2250G>A(p.Lys750Lys) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.0000423 in 1,608,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

ATM
NM_000051.4 splice_region, synonymous

Scores

Splicing: ADA: 0.9997

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:28

Conservation

PhyloP100: 4.70

Variant links:

Genes affected

ATM (HGNC:795): (ATM serine/threonine kinase) The protein encoded by this gene belongs to the PI3/PI4-kinase family. This protein is an important cell cycle checkpoint kinase that phosphorylates; thus, it functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. This protein and the closely related kinase ATR are thought to be master controllers of cell cycle checkpoint signaling pathways that are required for cell response to DNA damage and for genome stability. Mutations in this gene are associated with ataxia telangiectasia, an autosomal recessive disorder. [provided by RefSeq, Aug 2010]

ATM links:

ATM (HGNC:):

ATM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PP5

Variant 11-108256340-G-A is Pathogenic according to our data. Variant chr11-108256340-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108256340-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.2250G>A	p.Lys750Lys	splice_region_variant, synonymous_variant	14/63	ENST00000675843.1	NP_000042.3	Q13315A0A024R3C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.2250G>A	p.Lys750Lys	splice_region_variant, synonymous_variant	14/63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000439

AC:

AN:

250736

Hom.:

AF XY:

0.0000590

AC XY:

AN XY:

135560

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000705

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.0000439

AC:

AN:

1456664

Hom.:

Cov.:

AF XY:

0.0000455

AC XY:

AN XY:

724736

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000532

Gnomad4 OTH exome

AF:

0.0000333

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152072

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000651

Hom.:

Bravo

AF:

0.0000264

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:28

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Sep 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 23, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	Jul 11, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2002	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	Sep 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 27, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	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. -

not provided

Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ATM: PM2, PS3:Moderate, PS4:Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 25, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Apr 28, 2022	PS4, PP3, PM2_SUP, PS3 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Feb 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 25, 2018	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. -

Hereditary cancer-predisposing syndrome

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 10, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 14, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Mar 20, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	Jun 17, 2020	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). -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Nov 03, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	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). -

Familial cancer of breast

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 17, 2024	This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9463314, 10330348]. -
Likely pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, no assertion criteria provided	research	King Laboratory, University of Washington	Sep 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 26, 2024	- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Malignant tumor of breast

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Benign

0.91

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.9

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.94

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.94

Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over