rs587776549

Variant names:

• chr11-108272813-ATC-TGAT
• rs587776549
• NM_000051.4:c.3245_3247delATCinsTGAT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM3 PM2_Supporting PVS1 PM5_Supporting

This summary comes from the ClinGen Evidence Repository: The ATM c.3245_3247delinsTGAT (p.His1082LeufsTer14) variant is absent in the GnomAD cohort (PM2_Supporting). This variant is expected to produce an NMD-prone transcript due to a nonsense or frameshifting event (PVS1). In the absence of potential splicing rescue mechanisms in ATM, all PVS1-eligble truncating variants are expected to be pathogenic based on the existence of known pathogenic C-terminal truncations in the last exon (PM5_Supporting). This variant has been observed in a homozygous and compound heterozygous state (confirmed) in multiple individuals with Ataxia-Telangiectasia (PMIDs: 9443866, 10980530, 10817650; PM3_Very-Strong). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. LINK:https://erepo.genome.network/evrepo/ui/classification/CA298025/MONDO:0016419/020

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 frameshift, missense
• Clinical Significance: Pathogenic reviewed by expert panel P:19 O:2
• Conservation: PhyloP100: 7.50
• Publications: 13 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]

ATM Gene-Disease associations (from GenCC):

• ATM-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• ataxia telangiectasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Laboratory for Molecular Medicine
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• gastric carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: 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.
• PM5: 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.3245_3247delATCinsTGAT	p.His1082LeufsTer14	frameshift missense	Exon 22 of 63	NP_000042.3
	ATM	NM_001351834.2		c.3245_3247delATCinsTGAT	p.His1082LeufsTer14	frameshift missense	Exon 23 of 64	NP_001338763.1	Q13315

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.3245_3247delATCinsTGAT	p.His1082LeufsTer14	frameshift missense	Exon 22 of 63	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.3245_3247delATCinsTGAT	p.His1082LeufsTer14	frameshift missense	Exon 23 of 64	ENSP00000388058.2	Q13315
	ATM	ENST00000531525.3	TSL:1	c.3245_3247delATCinsTGAT	p.His1082LeufsTer14	frameshift missense	Exon 22 of 30	ENSP00000434327.3	H0YDU7

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
5	-	-	not provided (6)
4	-	-	Ataxia-telangiectasia syndrome (4)
4	-	-	Familial cancer of breast (4)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast (2)
1	-	-	Ataxia-telangiectasia syndrome;C3469522:Breast cancer, susceptibility to (1)
1	-	-	ATM-related cancer predisposition (1)
1	-	-	ATM-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.5
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs587776549; hg19: chr11-108143540;