NM_000051.4:c.2250G>A

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+11 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

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:31 U:1
• Conservation: PhyloP100: 4.70
• Publications: 1 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: 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

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.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		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).
	PM2Absent/extremely low in population databases		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.
	PP3Computational evidence supports damaging effect		Splicing predictors (SpliceAI/dbscSNV) support splicing impact — moderate computational evidence (PP3); Splicing verdict: pathogenic (Moderate).; Germline computational verdict: not pathogenic.
	PP5Reputable source reports pathogenic		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_regionsynonymous	Exon 14 of 63	Prot: NP_000042.3
	ATM NM_001351834.2		c.2250G>A p.Lys750Lys	splice_regionsynonymous	Exon 15 of 64	Prot: NP_001338763.1 UniProt:

ATM NM_000051.4

MANE Select

HGVSc / HGVSpc.2250G>Ap.Lys750Lys

Exon rankExon 14 of 63

splice_regionsynonymous

Prot: NP_000042.3

ATM NM_001351834.2

HGVSc / HGVSpc.2250G>Ap.Lys750Lys

Exon rankExon 15 of 64

splice_regionsynonymous

Prot: NP_001338763.1UniProt: 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_regionsynonymous	Exon 14 of 63	Prot: ENSP00000501606.1 UniProt:
	ATM ENST00000452508.7	TSL:1	c.2250G>A p.Lys750Lys	splice_regionsynonymous	Exon 15 of 64	Prot: ENSP00000388058.2 UniProt:
	ATM ENST00000531525.3	TSL:1	c.2250G>A p.Lys750Lys	splice_regionsynonymous	Exon 14 of 30	Prot: ENSP00000434327.3 UniProt:

ATM ENST00000675843.1

MANE Select

HGVSc / HGVSpc.2250G>Ap.Lys750Lys

Exon rankExon 14 of 63

splice_regionsynonymous

Prot: ENSP00000501606.1UniProt: Q13315

ATM ENST00000452508.7

TSL:1

HGVSc / HGVSpc.2250G>Ap.Lys750Lys

Exon rankExon 15 of 64

splice_regionsynonymous

Prot: ENSP00000388058.2UniProt: Q13315

ATM ENST00000531525.3

TSL:1

HGVSc / HGVSpc.2250G>Ap.Lys750Lys

Exon rankExon 14 of 30

splice_regionsynonymous

Prot: ENSP00000434327.3UniProt: H0YDU7

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000263	AC:4	Hom:0	AN:152072	Cov:32
GnomAD2 exomes	AF: 0.0000439	AC:11	Hom:	AN:250736	Cov:
GnomAD4 exome	AF: 0.0000439	AC:64	Hom:0	AN:1456664	Cov:30
GnomAD4 genome	AF: 0.0000263	AC:4	Hom:0	AN:152072	Cov:32
TOPMed (Bravo)	AF: 0.0000264	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000504	AC:15	Hom:0	AN:297492	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
ESP6500 (Exome Variant Server)	AF: 0.0000769	AC:1	Hom:	AN:12998	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.00	0	27890	0.0000706	2	28348
Epi25(Epilepsy)	0.0000485	2	41246	0.000121	8	65868
SCHEMA(Schizophrenia)	0.0000116	1	85906	0.0000508	7	137692

Showing 3 cohortsAllele 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

Pathogenic	VUS	Benign	Condition
10	-	-	Ataxia-telangiectasia syndrome (10)
7	-	-	not provided (7)
6	-	-	Hereditary cancer-predisposing syndrome (6)
4	-	-	Familial cancer of breast (4)
1	-	-	Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast (1)
1	-	-	Ataxia-telangiectasia syndrome;CN377759:ATM-related cancer predisposition (1)
1	-	-	ATM-related cancer predisposition (1)
-	1	-	Inherited breast cancer and ovarian cancer (1)
1	-	-	Malignant tumor of breast (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	25
BayesDel_noAF	Benign	-0.18
CADD	Benign	19
DANN	Benign	0.91
GPN-Star LLR	N/A	-6.2
GPN-Star score	N/A	6.2
Mutation Taster	N/A	3/97	disease causing (ClinVar)
PhyloP100	Uncertain	4.7
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	2.9

Showing 10 of 10 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
DS_DL_spliceai	Pathogenic	0.94	Position offset: 0
Pangolin (max)	Pathogenic	0.79
Pangolin loss	Pathogenic	0.79	Position offset: 0
SpliceAI score (max)	Pathogenic	0.94	Details are displayed if max score is > 0.2
Splicevardb	N/A	3.0

Showing 7 of 7 scores

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1137887;

hg19: chr11-108127067;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar