chr11-108330261-T-C

Variant names:

• chr11-108330261-T-C
• rs1555123032
• NM_000051.4:c.7355T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PP3 PM2_Supporting PM3_Strong PS3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.7355T>C variant in ATM is a missense variant predicted to cause substitution of leucine by proline at amino acid 2452 (p.Leu2452Pro). This variant has been detected in at least two individuals with Ataxia-Telangiectasia (PMIDs: 19431188, 26896183). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000001695 in the European (non-Finnish) population, which is lower than the HBOP threshold (≤0.00001) for PM2_Supporting, meeting this criterion. 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 REVEL gives a score of 0.914, which is above the threshold of 0.733, evidence that correlates with impact to ATM function. In summary, this variant meets the criteria to be classified as likely 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_Strong, PM2_Supporting, PS3_Supporting, PP3) LINK:https://erepo.genome.network/evrepo/ui/classification/CA382559953/MONDO:0700270/020

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:3
• Conservation: PhyloP100: 7.56
• Publications: 1 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: Likely_pathogenic. The variant received 7 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.
• PP3: 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.7355T>C	p.Leu2452Pro	missense	Exon 50 of 63	NP_000042.3
	ATM	NM_001351834.2		c.7355T>C	p.Leu2452Pro	missense	Exon 51 of 64	NP_001338763.1	Q13315
	C11orf65	NM_001330368.2		c.641-21190A>G		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.7355T>C	p.Leu2452Pro	missense	Exon 50 of 63	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.7355T>C	p.Leu2452Pro	missense	Exon 51 of 64	ENSP00000388058.2	Q13315
	ATM	ENST00000527805.6	TSL:1	n.*2419T>C		non_coding_transcript_exon	Exon 48 of 61	ENSP00000435747.2	E9PIN0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461842 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727222

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	-	Ataxia-telangiectasia syndrome (2)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	ATM-related cancer predisposition (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.6
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.79		Gain of disorder (P = 0.0165)
MVP		0.99
MPC		0.74
ClinPred		0.98	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.79
Mutation Taster		=3/97	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1555123032; hg19: chr11-108200988; COSMIC: COSV53744079; COSMIC: COSV53744079;