chr11-108365356-G-GA

Variant names:

• chr11-108365356-G-GA
• rs876660235
• NM_000051.4:c.9021dupA

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_000051.4(ATM):​c.9021dupA​(p.Arg3008ThrfsTer55) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000277484: Functional analysis of a lymphoblastoid cell line derived from a compound heterozygous patient with ataxia telangiectasia (AT) suggests this alteration results in deficient ATM protein and a double-strand break repair pattern resembling MRN-complex dysfunction. Authors note that the individual from whom this cell line was derived was older than 60 years with an attenuated or variant form of AT with moderate radiosensitivity, chromosomal instability, and cancer proneness (Keimling M et al. FASEB J. 2011 Nov" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R3008R) has been classified as Likely benign. The gene ATM is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.08
• Publications: 4 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 22 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 57 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000277484: Functional analysis of a lymphoblastoid cell line derived from a compound heterozygous patient with ataxia telangiectasia (AT) suggests this alteration results in deficient ATM protein and a double-strand break repair pattern resembling MRN-complex dysfunction. Authors note that the individual from whom this cell line was derived was older than 60 years with an attenuated or variant form of AT with moderate radiosensitivity, chromosomal instability, and cancer proneness (Keimling M et al. FASEB J. 2011 Nov; 25(11):3849-60).; SCV000622878: Experimental studies have shown that this frameshift affects ATM function (PMID: 21778326).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-108365356-G-GA is Pathogenic according to our data. Variant chr11-108365356-G-GA is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 233164.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.9021dupA	p.Arg3008ThrfsTer55	frameshift	Exon 63 of 63	NP_000042.3
	ATM	NM_001351834.2		c.9021dupA	p.Arg3008ThrfsTer55	frameshift	Exon 64 of 64	NP_001338763.1	Q13315
	C11orf65	NM_001330368.2		c.640+20563dupT		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.9021dupA	p.Arg3008ThrfsTer55	frameshift	Exon 63 of 63	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.9021dupA	p.Arg3008ThrfsTer55	frameshift	Exon 64 of 64	ENSP00000388058.2	Q13315
	C11orf65	ENST00000615746.4	TSL:1	c.*2-9248dupT		intron	N/A	ENSP00000483537.1	Q8NCR3-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Familial cancer of breast (2)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	Ataxia-telangiectasia syndrome (1)
1	-	-	Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.1
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs876660235; hg19: chr11-108236083;