rs587781353

Variant names:

• chr11-108345889-TG-AA
• rs587781353
• NM_000051.4:c.8565_8566delTGinsAA

Variant summary

Our verdict is Pathogenic. The variant received 4 ACMG points: 4P and 0B. PM2_Supporting PM3 PS3_Supporting

This summary comes from the ClinGen Evidence Repository: The ATM c.8565_8566delinsAA variant is predicted to cause a change in the length of the protein due to an in-frame deletion of one amino acid and an insertion of two amino acids in a non-repeat region (p.Ser2855_Val2856delinsArgIle). This variant has been detected in multiple unrelated individuals with Ataxia-Telangiectasia (PMIDs: 9872980, 10817650, 12673797, 26896183, 37438524). This variant is absent from gnomAD v4.1.0. Western blotting in ATM null cells transfected with cDNA carrying this variant showed inactive phosphorylation of ATM downstream targets as compared to wild-type controls indicating that this variant impacts protein function (PMID:19431188). The computational predictor Provean gives a score of -4.871, evidence that correlates with impact to ATM function. In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant ATM-related cancer predisposition and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (PM3_Very Strong, PM2_Supporting, PS3_Supporting). LINK:https://erepo.genome.network/evrepo/ui/classification/CA293967/MONDO:0700270/020

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 9.98
• Publications: 0 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

Our verdict: Pathogenic. The variant received 4 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.

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.8565_8566delTGinsAA	p.SerVal2855ArgIle	missense	N/A	NP_000042.3
	ATM	NM_001351834.2		c.8565_8566delTGinsAA	p.SerVal2855ArgIle	missense	N/A	NP_001338763.1	Q13315
	C11orf65	NM_001330368.2		c.641-36819_641-36818delCAinsTT		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.8565_8566delTGinsAA	p.SerVal2855ArgIle	missense	N/A	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.8565_8566delTGinsAA	p.SerVal2855ArgIle	missense	N/A	ENSP00000388058.2	Q13315
	C11orf65	ENST00000615746.4	TSL:1	c.*1196+9025_*1196+9026delCAinsTT		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

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Familial cancer of breast (2)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	Ataxia-telangiectasia syndrome (1)
1	-	-	ATM-related cancer predisposition (1)
1	-	-	ATM-related disorder (1)
1	-	-	Malignant tumor of breast (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		10
Mutation Taster		=3/197	disease causing

Splicing

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

Other links and lift over

dbSNP: rs587781353; hg19: chr11-108216616;