11-108330261-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

Selected	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
	C11orf65	NM_001330368.2		c.641-21190A>G		intron	N/A	NP_001317297.1

Ensembl Transcripts

Selected	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
	ATM	ENST00000452508.7	TSL:1	c.7355T>C	p.Leu2452Pro	missense	Exon 51 of 64	ENSP00000388058.2
	ATM	ENST00000527805.6	TSL:1	n.*2419T>C		non_coding_transcript_exon	Exon 48 of 61	ENSP00000435747.2

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

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

May 23, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces leucine with proline at codon 2452 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant disrupted kinase activity (PMID: 19431188, 26896183). This variant has been observed in two individuals affected with autosomal recessive ataxia-telangiectasia, one of which was confirmed in the compound heterozygous state with a second pathogenic variant, indicating that this variant contributes to disease (PMID: 19431188, 26896183). This variant was also detected in a breast cancer case-control analysis (PMID: 21787400). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

Jan 28, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L2452P variant (also known as c.7355T>C), located in coding exon 49 of the ATM gene, results from a T to C substitution at nucleotide position 7355. The leucine at codon 2452 is replaced by proline, an amino acid with similar properties. This alteration was identified in a patient with ataxia telangiectasia in conjunction with another ATM alteration, c.7638_7646del9 (Jackson TJ et al. Dev Med Child Neurol. 2016 07;58:690-7). In a functional study, this alteration showed loss of kinase activity (Barone G et al. Hum. Mutat. 2009 Aug;30:1222-30). This alteration has also been identified in 1 of 2570 Caucasian breast cancer cases and 0 of 1448 controls (Goldgar DE et al. Breast Cancer Res. 2011 Jul;13:R73). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Ataxia-telangiectasia syndrome Uncertain:2

Nov 30, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

May 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 2452 of the ATM protein (p.Leu2452Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ataxia-telangiectasia (PMID: 19431188, 26896183). ClinVar contains an entry for this variant (Variation ID: 481101). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ATM function (PMID: 19431188). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

ATM-related cancer predisposition Pathogenic:1

Jun 11, 2025

ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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)

not specified Uncertain:1

Sep 13, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATM c.7355T>C (p.Leu2452Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251270 control chromosomes (gnomAD). c.7355T>C has been reported in the literature as a compound heterozygous genotype in at least one individual affected with Ataxia-Telangiectasia and has been found in at least one individual undergoing ATM sequencing for breast cancer risk (e.g. Barone_2009, Jackson_2016, Goldgar_2011). These report(s) do not provide unequivocal conclusions about association of the variant with disease. At least one publication reports experimental evidence evaluating an impact on protein function. It was found that the variant ATM protein had little to no detectable kinase activity toward downstream targets in an expression model system (e.g. Barone_2009). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS - possibly pathogenic.

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;