rs1137887

Variant names:

• chr11-108256340-G-A
• rs1137887
• NM_000051.4:c.2250G>A
• ATM p.Lys750Lys

Your query was ambiguous. Multiple possible variants found:

• chr11-108256340-G-A
• chr11-108256340-G-C
• chr11-108256340-G-T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3 PP3 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 (★★). ClinVar reports functional evidence for this variant: "SCV000166090: Studies have shown that this variant is associated with altered splicing resulting in multiple RNA products (internal data)." and additional evidence is available in ClinVar. The gene ATM is included in the ClinGen Criteria Specification Registry.

• 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:30
• Conservation: PhyloP100: 4.70
• Publications: 28 publications found

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 Gene-Disease associations (from GenCC):

• ATM-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• ataxia telangiectasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Laboratory for Molecular Medicine, Genomics England PanelApp, G2P, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• gastric carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Specifications for ATM are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000166090: Studies have shown that this variant is associated with altered splicing resulting in multiple RNA products (internal data).; SCV002572759: Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 10330348 , 10980530 , 9463314 , 9887333).; SCV000183940: RNA studies have demonstrated that this alteration results in the same splicing event reported in the literature (Ambry internal data).; SCV000821696: This variant 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).; SCV001911500: 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).; SCV000149058: 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); 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; SCV004026020: PS3; SCV004220083: 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)).; SCV001549729: 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).
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-108256340-G-A is Pathogenic according to our data. Variant chr11-108256340-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000051.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	NM_000051.4	MANE Select	c.2250G>A	p.Lys750Lys	splice_region synonymous	Exon 14 of 63	NP_000042.3
	ATM	NM_001351834.2		c.2250G>A	p.Lys750Lys	splice_region synonymous	Exon 15 of 64	NP_001338763.1	Q13315

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.2250G>A	p.Lys750Lys	splice_region synonymous	Exon 14 of 63	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.2250G>A	p.Lys750Lys	splice_region synonymous	Exon 15 of 64	ENSP00000388058.2	Q13315
	ATM	ENST00000531525.3	TSL:1	c.2250G>A	p.Lys750Lys	splice_region synonymous	Exon 14 of 30	ENSP00000434327.3	H0YDU7

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152072 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000439 AC: 11 AN: 250736 AF XY: 0.0000590

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000705

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.0000439 AC: 64 AN: 1456664 Hom.: 0 Cov.: 30 AF XY: 0.0000455 AC XY: 33 AN XY: 724736

African (AFR) AF: 0.00 AC: 0 AN: 33388

American (AMR) AF: 0.0000224 AC: 1 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25992

East Asian (EAS) AF: 0.00 AC: 0 AN: 39454

South Asian (SAS) AF: 0.00 AC: 0 AN: 85886

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52876

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5736

European-Non Finnish (NFE) AF: 0.0000532 AC: 59 AN: 1108622

Other (OTH) AF: 0.0000333 AC: 2 AN: 60078

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152072 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74302

African (AFR) AF: 0.00 AC: 0 AN: 41408

American (AMR) AF: 0.0000656 AC: 1 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000478 Hom.: 0

Bravo AF: 0.0000264

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
10	-	-	Ataxia-telangiectasia syndrome (10)
6	-	-	Hereditary cancer-predisposing syndrome (6)
6	-	-	not provided (6)
4	-	-	Familial cancer of breast (4)
1	-	-	Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast (1)
1	-	-	ATM-related cancer predisposition (1)
1	-	-	Inherited breast cancer and ovarian cancer (1)
1	-	-	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.18
CADD	Benign	19
DANN	Benign	0.91
PhyloP100		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
Splicevardb		3.0
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1137887;

hg19: chr11-108127067;