11-108335958-T-G

Variant names:

• chr11-108335958-T-G
• rs758654836
• NM_000051.4:c.8265T>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000051.4(ATM):​c.8265T>G​(p.Tyr2755*) variant causes a stop gained change involving the alteration of a non-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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y2755Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: -0.0670
• Publications: 4 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.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-108335958-T-G is Pathogenic according to our data. Variant chr11-108335958-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 246093.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.8265T>G	p.Tyr2755*	stop_gained	Exon 56 of 63	NP_000042.3
	ATM	NM_001351834.2		c.8265T>G	p.Tyr2755*	stop_gained	Exon 57 of 64	NP_001338763.1
	C11orf65	NM_001330368.2		c.641-26887A>C		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.8265T>G	p.Tyr2755*	stop_gained	Exon 56 of 63	ENSP00000501606.1
	ATM	ENST00000452508.7	TSL:1	c.8265T>G	p.Tyr2755*	stop_gained	Exon 57 of 64	ENSP00000388058.2
	ATM	ENST00000527805.6	TSL:1	n.*3329T>G		non_coding_transcript_exon	Exon 54 of 61	ENSP00000435747.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:1

May 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 246093). This premature translational stop signal has been observed in individual(s) with clinical features of ATM-related conditions (PMID: 22213089, 25428789, 28726808). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr2755*) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872).

Inherited breast cancer and ovarian cancer Pathogenic:1

Aug 06, 2025

Genetics Laboratory, Great Ormond Street Hospital NHS Foundation Trust, North Thames Genomic Laboratory Hub

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_moderate, PVS1_very-strong, PM5_supporting

not provided Pathogenic:1

Dec 07, 2015

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This pathogenic variant is denoted ATM c.8265T>G at the cDNA level and p.Tyr2755Ter (Y2755X) at the protein level. The substitution creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAT>TAG) , and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in at least one case of early onset breast cancer (Churpek 2015) and is considered pathogenic.

Hereditary cancer-predisposing syndrome Pathogenic:1

Jan 10, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Y2755* pathogenic mutation (also known as c.8265T>G), located in coding exon 55 of the ATM gene, results from a T to G substitution at nucleotide position 8265. This changes the amino acid from a tyrosine to a stop codon within coding exon 55. This mutation was detected in an African American breast cancer patient diagnosed at age 29 (Churpek JE et al. Breast Cancer Res Treat, 2015 Jan;149:31-9). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

Familial cancer of breast Pathogenic:1

Feb 01, 2024

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	29
DANN	Benign	0.97
Eigen	Benign	-0.080
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.81	D
PhyloP100		-0.067
Vest4		0.94
GERP RS		-6.5
Mutation Taster		=0/200	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: rs758654836; hg19: chr11-108206685; COSMIC: COSV107219488; COSMIC: COSV107219488;