11-108365208-C-T

Variant names:

• chr11-108365208-C-T
• rs770641163
• NM_000051.4:c.8977C>T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_Very_Strong

The NM_000051.4(ATM):​c.8977C>T​(p.Arg2993*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,884 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000216664: AtM was not expressed in the cell line generated from a Spanish A-T patient who was compound heterozygous for this mutation and a second truncating mutation (Carranza D et al. Neuromolecular Med. 2017 Mar" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R2993R) has been classified as Likely benign. The gene ATM is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: ATM NM_000051.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:20 O:1
• Conservation: PhyloP100: 1.84
• Publications: 27 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 20 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 70 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000216664: AtM was not expressed in the cell line generated from a Spanish A-T patient who was compound heterozygous for this mutation and a second truncating mutation (Carranza D et al. Neuromolecular Med. 2017 Mar;19:161-174).; SCV000283099: Experimental studies have shown that this premature translational stop signal affects ATM function (PMID: 23774824).; SCV005621458: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 23774824); SCV001443743: Functional studies performed on cells derived from a patient with the c.8977C>T (p.Arg2993Ter) variant in the homozygous state and affected with Ataxia Telangiectasia showed loss of kinase activity (PMID: 23774824).
• PP5: Variant 11-108365208-C-T is Pathogenic according to our data. Variant chr11-108365208-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 186330.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.8977C>T	p.Arg2993*	stop_gained	Exon 62 of 63	NP_000042.3
	ATM	NM_001351834.2		c.8977C>T	p.Arg2993*	stop_gained	Exon 63 of 64	NP_001338763.1	Q13315
	C11orf65	NM_001330368.2		c.640+20712G>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.8977C>T	p.Arg2993*	stop_gained	Exon 62 of 63	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.8977C>T	p.Arg2993*	stop_gained	Exon 63 of 64	ENSP00000388058.2	Q13315
	C11orf65	ENST00000615746.4	TSL:1	c.*2-9099G>A		intron	N/A	ENSP00000483537.1	Q8NCR3-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251400 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: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727242

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

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1112008

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

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000141 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	not provided (6)
5	-	-	Ataxia-telangiectasia syndrome (5)
3	-	-	Hereditary cancer-predisposing syndrome (3)
2	-	-	Familial cancer of breast (2)
1	-	-	Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast (1)
1	-	-	Breast cancer, susceptibility to (1)
1	-	-	Hereditary breast ovarian cancer syndrome (1)
1	-	-	Koolen-de Vries syndrome (1)
-	-	-	Neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.97	D
PhyloP100		1.8
Vest4		0.74
GERP RS		3.4
Mutation Taster		=1/199	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: rs770641163; hg19: chr11-108235935; COSMIC: COSV53732836; COSMIC: COSV53732836;