rs267606668

Variant names:

• chr11-108332848-TG-GC
• rs267606668
• NM_000051.4:c.7875_7876delTGinsGC

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PM1 PP5_Very_Strong

The NM_000051.4(ATM):​c.7875_7876delTGinsGC​(p.AspAla2625GluPro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000187263: In one study, this variant was associated with complete absence of ATM protein in one homozygous AT patient (Becker-Catania SG et al. Mol. Genet. Metab. 2000 Jun" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position has been classified as Pathogenic. The gene ATM is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: 6.92
• Publications: 3 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 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000187263: In one study, this variant was associated with complete absence of ATM protein in one homozygous AT patient (Becker-Catania SG et al. Mol. Genet. Metab. 2000 Jun;70(2):122-33), while a second study detected ATM protein, but no ATM kinase activity in four homozygous AT patients (Verhagen MM et al. Hum. Mutat. 2012 Mar;33(3):561-71).; SCV000682438: Cells derived from some of these individuals have shown reduced ATM kinase activity (PMID: 22213089, 30549301, 31050087).; SCV000546759: Experimental studies have shown that this variant affects ATM function (PMID: 22213089).; SCV006077252: PS3:Supporting
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 37 uncertain in NM_000051.4
• PP5: Variant 11-108332848-TG-GC is Pathogenic according to our data. Variant chr11-108332848-TG-GC is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3030.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.7875_7876delTGinsGC	p.AspAla2625GluPro	missense	N/A	NP_000042.3
	ATM	NM_001351834.2		c.7875_7876delTGinsGC	p.AspAla2625GluPro	missense	N/A	NP_001338763.1	Q13315
	C11orf65	NM_001330368.2		c.641-23778_641-23777delCAinsGC		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.7875_7876delTGinsGC	p.AspAla2625GluPro	missense	N/A	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.7875_7876delTGinsGC	p.AspAla2625GluPro	missense	N/A	ENSP00000388058.2	Q13315
	C11orf65	ENST00000615746.4	TSL:1	c.*1270-1282_*1270-1281delCAinsGC		intron	N/A	ENSP00000483537.1	Q8NCR3-1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Ataxia-telangiectasia syndrome (6)
5	-	-	Familial cancer of breast (5)
2	-	-	Hereditary cancer-predisposing syndrome (2)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.9
Mutation Taster		=2/198	disease causing

Splicing

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

Other links and lift over

dbSNP: rs267606668; hg19: chr11-108203575;