rs11212587

Variant names:

• chr11-108315883-G-A
• rs11212587
• NM_000051.4:c.6067G>A
• ATM p.Gly2023Arg

Your query was ambiguous. Multiple possible variants found:

• chr11-108315883-G-A
• chr11-108315883-G-C

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

-8 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -8 classification points (ACMG Germline Pathogenicity v2019). BS2BP6_Strong

The NM_000051.4(ATM):c.6067G>A (p.Gly2023Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00155 (AC=2,496) in the gnomAD database across 1,612,772 control chromosomes, including 4 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.00197. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.47). Variant has been reported in ClinVar as Benign/Likely Benign (no review stars). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.G2023E: Uncertain_significance (ClinVar VariationId 453610, 2 stars); p.G2023= (synonymous): Likely_benign (ClinVar VariationId 1751358, 1 star); p.G2023R: Benign (ClinVar VariationId 2127852, 1 star); p.G2023V: Uncertain_significance (ClinVar VariationId 3801988, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance, associated with Ataxia telangiectasia (AT).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (4 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:6 B:26 O:3
• Conservation: PhyloP100: 9.47
• Publications: 68 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

C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

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.

Our verdict: Benign. The variant received -8 points.

• BP6: ClinVar 0-star benign — supporting (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 0 star(s). ClinVar submissions strongly and reliably favor benignity (22/27 total B/LB).
• BS2: ≥2 homozygotes in gnomAD — observed in healthy adults (BS2); GnomAD homozygous count = 4.; Very high cumulative gnomAD AC = 2496 (any gene).

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.6067G>A	p.Gly2023Arg	missense	Exon 41 of 63	NP_000042.3
	ATM	NM_001351834.2		c.6067G>A	p.Gly2023Arg	missense	Exon 42 of 64	NP_001338763.1	Q13315
	C11orf65	NM_001330368.2		c.641-6812C>T		intron	N/A	NP_001317297.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.6067G>A	p.Gly2023Arg	missense	Exon 41 of 63	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.6067G>A	p.Gly2023Arg	missense	Exon 42 of 64	ENSP00000388058.2	Q13315
	ATM	ENST00000527805.6	TSL:1	n.*1131G>A		3_prime_UTR	Exon 39 of 61	ENSP00000435747.2	E9PIN0

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	0.00125	190	0	152136	32
GnomAD2 exomes	0.00143	360		251402
GnomAD4 exome	0.00158	2306	4	1460518	32
GnomAD4 genome	0.00125	190	0	152254	32
TOPMed (Bravo)	0.00132	350	0	264690
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	0.00196	1308	5	667622
Local & regional cohorts 8 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	0.00128	3	0	2342
ChinaMAP Phase 1	0.000148
ESP6500 (Exome Variant Server)	0.00231	30		12998
GenomeAsia100K	0.000289	1		3478
ToMMo 61KJPN (+60KJPN MNV)	0.00000800	1	0	122712
Turkish Variome	0.00164	11	0	6714
UK10K	0.00225	17		7562
WBBC (Westlake BioBank for Chinese) pilot	0.000223	2	0	8960

Showing 14 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.00243 *	27	11110	0.00210 *	37	17616
BipEx(Bipolar disorder (including schizoaffective))	0.00274	78	28420	0.00253	73	28844
Epi25(Epilepsy)	0.00205	86	41958	0.00158	106	66888
SCHEMA(Schizophrenia)	0.00178	217	122062	0.00351	672	191448

Showing 4 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	not provided (11)
-	3	4	Hereditary cancer-predisposing syndrome (7)
-	1	4	Ataxia-telangiectasia syndrome (6)
-	1	2	Familial cancer of breast (3)
-	-	3	not specified (4)
-	-	1	ATM-related cancer predisposition (1)
-	-	1	Breast and/or ovarian cancer (1)
-	1	-	Hereditary breast ovarian cancer syndrome (1)
-	-	1	Malignant tumor of breast (1)
1	-	-	Tip-toe gait (1)

Computational Scores

Algorithm	Calibrated prediction	Prediction	Score
AlphaGenome AVI	Pathogenic	-	26
AlphaMissense	Uncertain	-	0.42
BayesDel_addAF	Benign	T	-0.11
BayesDel_noAF	Uncertain	-	0.070
CADD	Uncertain	-	26
DANN	Pathogenic	-	1.0
DEOGEN2	Benign	T	0.14
Eigen	Pathogenic	-	0.80
Eigen_PC	Pathogenic	-	0.78
FATHMM_MKL	Pathogenic	D	0.99
FuncVEP CTI	Benign	-	0.082
GPN-Star LLR	N/A	-	-8.5
GPN-Star score	N/A	-	8.5
LIST_S2	Uncertain	D	0.94
M_CAP	Uncertain	D	0.28
MetaRNN	Benign	T	0.16
MetaSVM	Benign	T	-1.1
Mutation Taster	N/A	disease causing	12/88
MutationAssessor	Uncertain	M	2.6
PhyloP100	Pathogenic	-	9.5
PrimateAI	Uncertain	T	0.66
PROVEAN	Uncertain	D	-3.5
RBP_binding_hub_radar	N/A	-	0.0
RBP_regulation_power_radar	N/A	-	1.7
REVEL	Uncertain	-	0.51
Sift	Uncertain	D	0.0030
Sift4G	Uncertain	D	0.0030
Varity_R	N/A	-	0.81
VESM-3B	Benign	-	-8.2

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated prediction	Prediction	Score
Pangolin (max)	Benign	-	0.17
Pangolin loss	Benign	- Position offset: 28	0.17
SpliceAI score (max)	Benign	- Details are displayed if max score is > 0.2	0.010

Showing 3 of 3 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.

Other links and lift over

dbSNP: rs11212587;

hg19: chr11-108186610;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar