rs587776547

Variant names:

• chr11-108331884-CTCTAGAATT-C
• rs587776547
• NM_000051.4:c.7638_7646delTAGAATTTC

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PM4 PP5_Very_Strong

The NM_000051.4(ATM):​c.7638_7646delTAGAATTTC​(p.Arg2547_Ser2549del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000626 in 1,613,216 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000186502: Further, functional analysis has shown that this mutation results in intact ATM protein expression but no kinase activity (Stewart GS et al. J. Biol. Chem. 2001 Aug" and additional evidence is available in ClinVar. The gene ATM is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: ATM NM_000051.4 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:28 U:1
• Conservation: PhyloP100: 3.51
• Publications: 7 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: SCV000186502: Further, functional analysis has shown that this mutation results in intact ATM protein expression but no kinase activity (Stewart GS et al. J. Biol. Chem. 2001 Aug;276:30133-41).; SCV000682427: Functional studies have reported the mutant protein to show a severely defective kinase activity (PMID: 11382771, 19431188, 21778326, 22649200).; SCV000262210: Experimental studies have shown that this variant affects ATM function (PMID: 11382771, 12195425, 19431188, 22649200).; SCV000916557: Functional studies confirmed that there is no detectable ATM kinase activity associated with this variant and that LCLs with this variant exhibited p53, p21, and MDM2 response that was indistinguishable from classical A-T (Stewart_2001).; SCV005689224: Functional studies have shown that this variant results in no detectable kinase activity (PMID: 19431188).; SCV000209607: Published functional studies demonstrate a damaging effect: absence of kinase activity and reduced ATM protein expression (Stewart et al., 2001; Barone et al., 2009; Reiman et al., 2011); SCV005620742: Assessment of experimental evidence suggests this variant results in abnormal protein function. PMID: 19431188; SCV000839880: Functional assays showed that the variant does not affect the level of ATM protein but does reduce the level of kinase activity [PMID 19431188].; SCV004932506: Functional studies indicate this variant impacts protein function [PMID: 19431188].; SCV001550193: Multiple functional studies have shown the ATM protein lacks kinase activity and is expressed at low levels, confirming the pathogenicity of this variant (Barone 2009, Reiman 2011).; SCV000805616: In vitro functional analysis showed that this variant had no kinase activity (Barone et al. 2009. PubMed ID: 19431188).
• PM4: Nonframeshift variant in NON repetitive region in NM_000051.4.
• PP5: Variant 11-108331884-CTCTAGAATT-C is Pathogenic according to our data. Variant chr11-108331884-CTCTAGAATT-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 3019.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.7638_7646delTAGAATTTC	p.Arg2547_Ser2549del	disruptive_inframe_deletion	Exon 52 of 63	NP_000042.3
	ATM	NM_001351834.2		c.7638_7646delTAGAATTTC	p.Arg2547_Ser2549del	disruptive_inframe_deletion	Exon 53 of 64	NP_001338763.1	Q13315
	C11orf65	NM_001330368.2		c.641-22822_641-22814delAATTCTAGA		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.7638_7646delTAGAATTTC	p.Arg2547_Ser2549del	disruptive_inframe_deletion	Exon 52 of 63	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.7638_7646delTAGAATTTC	p.Arg2547_Ser2549del	disruptive_inframe_deletion	Exon 53 of 64	ENSP00000388058.2	Q13315
	C11orf65	ENST00000615746.4	TSL:1	c.*1270-326_*1270-318delAATTCTAGA		intron	N/A	ENSP00000483537.1	Q8NCR3-1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000279 AC: 7 AN: 251148 AF XY: 0.0000221

Gnomad AFR exome AF: 0.0000617

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: 0.0000529

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000678 AC: 99 AN: 1461142 Hom.: 0 AF XY: 0.0000784 AC XY: 57 AN XY: 726924

African (AFR) AF: 0.0000299 AC: 1 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

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

European-Non Finnish (NFE) AF: 0.0000837 AC: 93 AN: 1111444

Other (OTH) AF: 0.0000828 AC: 5 AN: 60360

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152074 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74278

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41400

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	-	-	Ataxia-telangiectasia syndrome (9)
6	-	-	not provided (6)
5	-	-	Familial cancer of breast (5)
4	-	-	Hereditary cancer-predisposing syndrome (4)
1	-	-	ATM-related disorder (1)
1	-	-	Breast and/or ovarian cancer (1)
-	1	-	Breast neoplasm (1)
1	-	-	Malignant tumor of breast (1)
1	-	-	T-cell prolymphocytic leukemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.5
Mutation Taster		=22/178	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs587776547; hg19: chr11-108202611; COSMIC: COSV53728446;