11-108256215-A-G

Variant names:

• chr11-108256215-A-G
• rs864622259
• NM_000051.4:c.2125A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000051.4(ATM):​c.2125A>G​(p.Ile709Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,450,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 19/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I709M) has been classified as Uncertain significance. The gene ATM is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ATM NM_000051.4 missense, splice_region
• Scores: Splicing: ADA: 0.00006122
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: -0.0420
• Publications: 4 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, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Laboratory for Molecular Medicine
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.040843546).

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.2125A>G	p.Ile709Val	missense splice_region	Exon 14 of 63	NP_000042.3
	ATM	NM_001351834.2		c.2125A>G	p.Ile709Val	missense splice_region	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.2125A>G	p.Ile709Val	missense splice_region	Exon 14 of 63	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.2125A>G	p.Ile709Val	missense splice_region	Exon 15 of 64	ENSP00000388058.2	Q13315
	ATM	ENST00000531525.3	TSL:1	c.2125A>G	p.Ile709Val	missense splice_region	Exon 14 of 30	ENSP00000434327.3	H0YDU7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1450994 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 721954

African (AFR) AF: 0.00 AC: 0 AN: 33322

American (AMR) AF: 0.00 AC: 0 AN: 44516

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25896

East Asian (EAS) AF: 0.00 AC: 0 AN: 39306

South Asian (SAS) AF: 0.00 AC: 0 AN: 84752

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52540

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1105116

Other (OTH) AF: 0.00 AC: 0 AN: 59820

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Ataxia-telangiectasia syndrome (2)
-	2	-	Hereditary cancer-predisposing syndrome (2)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.73
DANN	Benign	0.25
DEOGEN2	Benign	0.054	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.042
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.16	N
REVEL	Benign	0.12
Sift	Benign	0.62	T
Sift4G	Benign	0.97	T
Polyphen		0.0	B
Vest4		0.015
MutPred		0.078		Gain of disorder (P = 0.1087)
MVP		0.62
MPC		0.10
ClinPred		0.044	T
GERP RS		0.54
Varity_R		0.031
gMVP		0.041
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000061
dbscSNV1_RF	Benign	0.018
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs864622259; hg19: chr11-108126942;