11-108325416-C-T

Variant names:

• chr11-108325416-C-T
• rs564652222
• NM_000051.4:c.6679C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM1 PP3_Strong PP5_Very_Strong

The NM_000051.4(ATM):​c.6679C>T​(p.Arg2227Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,530 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: "SCV000218096: Further studies indicated that the p.R2227C alteration led to protein levels of only 20-35% of wild-type and nearly absent ATM kinase activity (Meissner WG et al. Mov. Disord. 2013 Nov" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2227H) has been classified as Uncertain significance. The gene ATM is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:24 O:2
• Conservation: PhyloP100: 5.38
• Publications: 30 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

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

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

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000218096: Further studies indicated that the p.R2227C alteration led to protein levels of only 20-35% of wild-type and nearly absent ATM kinase activity (Meissner WG et al. Mov. Disord. 2013 Nov;28:1897-9). Another group evaluated the effect of the p.R2227C variant on the cellular phenotype of a transfected and transduced host A-T cell line (AT7LA) and found only trace amounts of ATM protein were detectable.; SCV000687719: Functional studies have shown that this variant results in reduced ATM protein expression and kinase activity in cell-based assays (PMID: 18634022).; SCV000821702: recent functional studies of the mutant protein where they showed decreased expression of ATM and reduced ATM kinase activity (PMID: 23640770, PMID: 18634022 ); SCV001911477: Lymphoblastoid cell lines of patients carrying this variant have been reported to have residual or absent ATM protein expression, no detectable ATM p.Ser1981 autophosphorylation, almost absent transphosphorylation activity on SMC1 p.Ser957/p.Ser966 and intermediate or severe radiosensitivity (PS3_Moderate; PMID: 10873394, 18634022).; SCV000253742: Experimental studies have shown that this missense change affects ATM function (PMID: 18634022, 23640770).; SCV004812602: In vitro expression of the variant in an A-T (ATM null) cell line demonstrated failure-to-rescue target phosphorylation and intermediate radiosensitivity. PMID:18634022, 28126470, 32548172; SCV000209765: Published functional studies in patient cells demonstrate reduced ATM protein expression, reduced kinase activity, and increased radiosensitivity (Becker-Catania 2000, Mitui 2009, Meissner 2013, Fievet 2019); SCV001551568: Several functional studies of ATM protein levels in A-T patients showed the p.Arg2227Cys variant exhibited reduced ATM expression (Becker_Catania_2000, Mitui_2009).; SCV002065903: Experimental studies have demonstrated that this sequence change impacts the function of the ATM protein (PMID: 18634022, 23640770).; SCV001431897: Functional studies report this variant effect results in reducing ATM protein level, ATM kinase activity and shown as severe in radiation sensitivity (Mitui_2009, Meissner_2013).
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 43 uncertain in NM_000051.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 11-108325416-C-T is Pathogenic according to our data. Variant chr11-108325416-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 181981.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.6679C>T	p.Arg2227Cys	missense	Exon 46 of 63	NP_000042.3
	ATM	NM_001351834.2		c.6679C>T	p.Arg2227Cys	missense	Exon 47 of 64	NP_001338763.1	Q13315
	C11orf65	NM_001330368.2		c.641-16345G>A		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.6679C>T	p.Arg2227Cys	missense	Exon 46 of 63	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.6679C>T	p.Arg2227Cys	missense	Exon 47 of 64	ENSP00000388058.2	Q13315
	ATM	ENST00000527805.6	TSL:1	n.*1743C>T		non_coding_transcript_exon	Exon 44 of 61	ENSP00000435747.2	E9PIN0

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152006 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461524 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 727078

African (AFR) AF: 0.00 AC: 0 AN: 33474

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111776

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152006 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74252

African (AFR) AF: 0.0000483 AC: 2 AN: 41396

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000406 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
8	-	-	not provided (8)
7	-	-	Ataxia-telangiectasia syndrome (8)
4	-	-	Hereditary cancer-predisposing syndrome (4)
3	-	-	Familial cancer of breast (3)
1	-	-	Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast (1)
1	-	-	Malignant tumor of breast (1)
-	-	-	Neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		5.4
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.96		Gain of catalytic residue at M2224 (P = 0.1766)
MVP		0.98
MPC		0.68
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.83
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs564652222; hg19: chr11-108196143; COSMIC: COSV53730709; COSMIC: COSV53730709;