rs1137887

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is The variant received 11 classification points (ACMG Germline Pathogenicity v2019). PS3PM2_SupportingPP3_ModeratePP5_Strong

The NM_000051.4(ATM):c.2250G>A (p.Lys750Lys) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000423 (AC=68) in the gnomAD database across 1,608,736 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000612. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (no review stars). 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.

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

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:31U:1

Conservation

PhyloP100: 4.70

Publications

28 publications found

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 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: Natera, Ambry Genetics
ataxia telangiectasia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, ClinGen, G2P, Orphanet, Natera, PanelApp Australia, Ambry Genetics, 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

ATM links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000051.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

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

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 points.

PS3

Well-established functional study supports damaging effect (PS3); 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).

PM2

Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000612 — borderline rare for AD+AR gene (threshold 0.0001) — PM2 supporting.

PP3

Splicing predictors (SpliceAI/dbscSNV) support splicing impact — moderate computational evidence (PP3); Splicing verdict: pathogenic (Moderate).; Germline computational verdict: not pathogenic.

PP5

ClinVar 0-star pathogenic — supporting (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 0 star(s). ClinVar submissions strongly and reliably favor pathogenicity (26/27 total P/LP).

Variant Effect in Transcripts

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

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:

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

GnomAD2 exomes

AF:

0.0000439

AC:

AN:

250736

AF XY:

0.0000590

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 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

African (AFR)

AF:

0.00

AC:

AN:

33388

American (AMR)

AF:

0.0000224

AC:

AN:

44632

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25992

East Asian (EAS)

AF:

0.00

AC:

AN:

39454

South Asian (SAS)

AF:

0.00

AC:

AN:

85886

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52876

Middle Eastern (MID)

AF:

0.000349

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.0000532

AC:

AN:

1108622

Other (OTH)

AF:

0.0000333

AC:

AN:

60078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152072

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41408

American (AMR)

AF:

0.0000656

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

TOPMed (Bravo)

AF:

0.0000264

ALFA (dbGaP/dbSNP Allele Frequency Aggregator)

AF:

0.0000504

AC:

AN:

297492

Hom.:

Local populations

ESP6500 (Exome Variant Server)

AF:

0.0000769

AC:

AN:

12998

show subpopulations

European American

AF:

0.000116

AC:

AN:

8596

African American

AF:

0.00

AC:

AN:

4402

Case/control cohorts

Cohort

Cases

Controls

BipEx

(Bipolar disorder (including schizoaffective))

0 / 27890AF: 0

2 / 28348AF: 0.0000705517

Epi25

(Epilepsy)

2 / 41246AF: 0.0000484896

8 / 65868AF: 0.000121455

SCHEMA

(Schizophrenia)

1 / 85906AF: 0.0000116406

7 / 137692AF: 0.0000508381

Allele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Ataxia-telangiectasia syndrome (10)

not provided (7)

Hereditary cancer-predisposing syndrome (6)

Familial cancer of breast (4)

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast (1)

Ataxia-telangiectasia syndrome;CN377759:ATM-related cancer predisposition (1)

ATM-related cancer predisposition (1)

Inherited breast cancer and ovarian cancer (1)

Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Benign

0.91

PhyloP100

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.9

AlphaGenome AVI

Pathogenic

(source)

GPN-Star LLR

-6.2

(source)

GPN-Star score

6.2

(source)

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

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

Pangolin (max)

Pathogenic

0.79

(source)

Pangolin loss

0.79

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.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

Case/control cohorts

ClinVar

Computational scores

Splicing

Publications

Other links and lift over