11-108345819-G-T

Variant names:

• chr11-108345819-G-T
• rs529296539
• NM_000051.4:c.8495G>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000051.4(ATM):​c.8495G>T​(p.Arg2832Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2832S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.98
• Publications: 24 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 18 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 38 uncertain in NM_000051.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-108345818-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3720488.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965
• PP5: Variant 11-108345819-G-T is Pathogenic according to our data. Variant chr11-108345819-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 430406.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	NM_000051.4	MANE Select	c.8495G>T	p.Arg2832Leu	missense	Exon 58 of 63	NP_000042.3
	ATM	NM_001351834.2		c.8495G>T	p.Arg2832Leu	missense	Exon 59 of 64	NP_001338763.1
	C11orf65	NM_001330368.2		c.641-36748C>A		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.8495G>T	p.Arg2832Leu	missense	Exon 58 of 63	ENSP00000501606.1
	ATM	ENST00000452508.7	TSL:1	c.8495G>T	p.Arg2832Leu	missense	Exon 59 of 64	ENSP00000388058.2
	ATM	ENST00000527805.6	TSL:1	n.*3559G>T		non_coding_transcript_exon	Exon 56 of 61	ENSP00000435747.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:2

Apr 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 2832 of the ATM protein (p.Arg2832Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ataxia-telangiectasia (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 430406). 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. This variant disrupts the p.Arg2832 amino acid residue in ATM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9443866, 10817650, 10873394, 12552559, 18634022). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

May 21, 2025

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Pathogenic:2

May 16, 2024

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) This variant has been identified in at least one individual with clinical features associated with this gene. Multiple missense variants at this codon, including at least one considered to be pathogenic or likely pathogenic, have been reported in individuals with clinical features associated with this gene, suggesting this variant may also cause disease. Polyphen and MutationTaster predict this amino acid change may be damaging to the protein.

Oct 10, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in a patient with chronic lymphocytic leukemia; however, it is unclear if the variant was germline or somatic (Landau et al., 2015); This variant is associated with the following publications: (PMID: 23532176, 26466571, 36999792)

Hereditary cancer-predisposing syndrome Pathogenic:2

Feb 12, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with leucine at codon 2832 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with ataxia-telangiectasia (PMID: 37438524, ClinVar: SCV000622825.3, SCV002675381.2). Two different variant affecting the same codon, c.8494C>T (p.Arg2832Cys) and c.8495G>C (p.Arg2832Pro), are considered to be disease-causing (ClinVar variation IDs: 127459, 429065), suggesting that arginine at this position is important for the protein function. This variant, c.8495G>T (p.Arg2832Leu), 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.

Feb 12, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R2832L variant (also known as c.8495G>T), located in coding exon 57 of the ATM gene, results from a G to T substitution at nucleotide position 8495. The arginine at codon 2832 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in conjunction with another pathogenic ATM mutation in individuals with features of ataxia telangiectasia (AT) (correspondence with external clinical laboratories). This amino acid position is highly 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.

Familial cancer of breast Pathogenic:1

Feb 07, 2025

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 37438524, Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 18634022, 21792198]. This variant is expected to disrupt protein structure [Myriad internal data].

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		10
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.81		Gain of loop (P = 0.0435)
MVP		0.97
MPC		0.64
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.90
gMVP		0.83
Mutation Taster		=8/92	disease causing (ClinVar)

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: rs529296539; hg19: chr11-108216546; COSMIC: COSV105845326; COSMIC: COSV105845326;