11-108316030-G-A

Variant names:

• chr11-108316030-G-A
• rs864622251
• NM_000051.4:c.6115G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM2 PP3_Strong PP5_Very_Strong

The NM_000051.4(ATM):​c.6115G>A​(p.Glu2039Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000259858: Experimental studies have shown that this missense change affects ATM function (PMID:19431188, 22071889).; SCV000322164: Published functional studies demonstrate a damaging effect: reduced kinase activity compared to wild type (PMID:19431188, 22071889); Observed with a second ATM variant in patients with clinical features of ataxia-telangiectasia but it is not known whether the variants occurred on the same (in cis) or opposite (in trans) alleles (PMID:22071889, 30549301); SCV000667845: Additional investigation has demonstrated stable, normally-localized ATM protein, but reduced kinase activity associated with p.E2039K compared to wild type (Barone G et al. Hum. Mutat. 2009 Aug; 30(8):1222-30. Jacquemin V et al. Eur. J. Hum. Genet. 2012 Mar; 20(3):305-12).; SCV000908453: Functional studies have reported that this variant does not affect protein expression but causes a reduction in kinase activity (PMID:19431188).; SCV004931121: Functional studies indicate this variant impacts protein function [PMID:19431188, 30549301].; SCV004721134: Functional studies demonstrated reduced kinase activity (Barone et al. 2009. PubMed ID: 19431188) and defective response to ionizing radiation (Jacquemin et al. 2012. PubMed ID: 22071889).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E2039V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 U:1
• Conservation: PhyloP100: 9.22
• Publications: 23 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]

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]

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000259858: Experimental studies have shown that this missense change affects ATM function (PMID: 19431188, 22071889).; SCV000322164: Published functional studies demonstrate a damaging effect: reduced kinase activity compared to wild type (PMID: 19431188, 22071889); Observed with a second ATM variant in patients with clinical features of ataxia-telangiectasia but it is not known whether the variants occurred on the same (in cis) or opposite (in trans) alleles (PMID: 22071889, 30549301); SCV000667845: Additional investigation has demonstrated stable, normally-localized ATM protein, but reduced kinase activity associated with p.E2039K compared to wild type (Barone G et al. Hum. Mutat. 2009 Aug; 30(8):1222-30. Jacquemin V et al. Eur. J. Hum. Genet. 2012 Mar; 20(3):305-12).; SCV000908453: Functional studies have reported that this variant does not affect protein expression but causes a reduction in kinase activity (PMID: 19431188).; SCV004931121: Functional studies indicate this variant impacts protein function [PMID: 19431188, 30549301].; SCV004721134: Functional studies demonstrated reduced kinase activity (Barone et al. 2009. PubMed ID: 19431188) and defective response to ionizing radiation (Jacquemin et al. 2012. PubMed ID: 22071889).
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947
• PP5: Variant 11-108316030-G-A is Pathogenic according to our data. Variant chr11-108316030-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 219787.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.6115G>A	p.Glu2039Lys	missense	Exon 42 of 63	NP_000042.3
	ATM	NM_001351834.2		c.6115G>A	p.Glu2039Lys	missense	Exon 43 of 64	NP_001338763.1	Q13315
	C11orf65	NM_001330368.2		c.641-6959C>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.6115G>A	p.Glu2039Lys	missense	Exon 42 of 63	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.6115G>A	p.Glu2039Lys	missense	Exon 43 of 64	ENSP00000388058.2	Q13315
	ATM	ENST00000527805.6	TSL:1	n.*1179G>A		non_coding_transcript_exon	Exon 40 of 61	ENSP00000435747.2	E9PIN0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251392 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461846 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727224

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111988

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000426 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	1	-	Hereditary cancer-predisposing syndrome (4)
3	-	-	Familial cancer of breast (3)
1	-	-	Ataxia-telangiectasia syndrome (1)
1	-	-	ATM-related disorder (1)
1	-	-	Breast and/or ovarian cancer (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		9.2
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.81		Gain of MoRF binding (P = 0.0037)
MVP		0.97
MPC		0.24
ClinPred		0.92	D
GERP RS		5.2
Varity_R		0.23
gMVP		0.88
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs864622251; hg19: chr11-108186757; COSMIC: COSV53740536; COSMIC: COSV53740536;