11-108335080-G-T

Variant names:

• chr11-108335080-G-T
• rs587782719
• NM_000051.4:c.8122G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_000051.4(ATM):​c.8122G>T​(p.Asp2708Tyr) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2708V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 9.51
• Publications: 36 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 9 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, 43 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 chr11-108335081-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1021521.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918
• PP5: Variant 11-108335080-G-T is Pathogenic according to our data. Variant chr11-108335080-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 835131.

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.8122G>T	p.Asp2708Tyr	missense	Exon 55 of 63	NP_000042.3
	ATM	NM_001351834.2		c.8122G>T	p.Asp2708Tyr	missense	Exon 56 of 64	NP_001338763.1
	C11orf65	NM_001330368.2		c.641-26009C>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.8122G>T	p.Asp2708Tyr	missense	Exon 55 of 63	ENSP00000501606.1
	ATM	ENST00000452508.7	TSL:1	c.8122G>T	p.Asp2708Tyr	missense	Exon 56 of 64	ENSP00000388058.2
	ATM	ENST00000527805.6	TSL:1	n.*3186G>T		non_coding_transcript_exon	Exon 53 of 61	ENSP00000435747.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 251356 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Mar 10, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D2708Y variant (also known as c.8122G>T), located in coding exon 54 of the ATM gene, results from a G to T substitution at nucleotide position 8122. The aspartic acid at codon 2708 is replaced by tyrosine, an amino acid with highly dissimilar properties. Although this exact alteration has not been reported in the literature, two other alterations at this same amino acid codon (p.D2708E and p.D2708N) have been reported in the homozygous and compound heterozygous state in multiple individuals with ataxia-telengiectasia (A-T) (Heinrich T et al. Eur. J. Pediatr. 2006; 165:250-7; Magliozzi M et al. Dis. Markers 2006; 22(4):257-64; Cavalieri S et al. Ann. Hum. Genet. 2008;72(Pt 1):10-8; Micol R et al. J. Allergy Clin. Immunol. 2011 Aug;128(2):382-9.e1; Jacquemin V et al. Eur. J. Hum. Genet. 2012; 20:305-12; Claes K et al. Neuromolecular Med. 2013;15(3):447-57; Bisgin A et al. Biomed Res Int 2018 May;2018:9647253). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

not specified Uncertain:1

Sep 16, 2024

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.8122G>T (p.Asp2708Tyr) results in a non-conservative amino acid change located in the Phosphatidylinositol 3-/4-kinase, catalytic domain (IPR000403) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. To our knowledge, no occurrence of c.8122G>T in individuals affected with Prostate Cancer and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 835131). Based on the evidence outlined above, the variant was classified as uncertain significance.

Ataxia-telangiectasia syndrome Uncertain:1

Sep 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 2708 of the ATM protein (p.Asp2708Tyr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 835131). 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.Asp2708 amino acid residue in ATM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16411093, 16941484, 21665257, 22071889, 23454770, 23632773). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		9.5
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.62		Loss of disorder (P = 0.0191)
MVP		0.99
MPC		0.64
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.90
Mutation Taster		=9/91	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: rs587782719; hg19: chr11-108205807; COSMIC: COSV53785475;