11-108316060-T-G

Variant names:

• chr11-108316060-T-G
• rs786203767
• NM_000051.4:c.6145T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000051.4(ATM):​c.6145T>G​(p.Tyr2049Asp) variant causes a missense change. 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. Y2049C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:2
• Conservation: PhyloP100: 5.67
• Publications: 5 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 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 35 uncertain in NM_000051.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969
• PP5: Variant 11-108316060-T-G is Pathogenic according to our data. Variant chr11-108316060-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 187481.

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.6145T>G	p.Tyr2049Asp	missense	Exon 42 of 63	NP_000042.3
	ATM	NM_001351834.2		c.6145T>G	p.Tyr2049Asp	missense	Exon 43 of 64	NP_001338763.1
	C11orf65	NM_001330368.2		c.641-6989A>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.6145T>G	p.Tyr2049Asp	missense	Exon 42 of 63	ENSP00000501606.1
	ATM	ENST00000452508.7	TSL:1	c.6145T>G	p.Tyr2049Asp	missense	Exon 43 of 64	ENSP00000388058.2
	ATM	ENST00000527805.6	TSL:1	n.*1209T>G		non_coding_transcript_exon	Exon 40 of 61	ENSP00000435747.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:2 Uncertain:1

Jan 19, 2018

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.

Jan 30, 2025

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATM c.6145T>G (p.Tyr2049Asp) results in a non-conservative amino acid change located in the PIK-related kinase domain (IPR014009) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251404 control chromosomes. c.6145T>G has been reported in the literature in at-least four individuals affected with Ataxia-Telangiectasia as well as a VUS in settings of multigene panel testing among individuals with a variety of cancers (example, Podralska_2014, Maciejczyk_2019, Seligson_2019, Moens_2014, Pearlman_2021, Elitzur_2024). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31611883, 25502423, 34250417, 25614872, 30541756, 38917355). ClinVar contains an entry for this variant (Variation ID: 187481). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 2049 of the ATM protein (p.Tyr2049Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ataxia-telangiectasia (PMID: 25614872, 31611883). ClinVar contains an entry for this variant (Variation ID: 187481). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ATM protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Familial cancer of breast Pathogenic:2

Apr 09, 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: 38917355, 37438524, 31611883, 25614872].

Jan 26, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Pathogenic:2

May 31, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces tyrosine with aspartic acid at codon 2049 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 observed in the compound heterozygous state in individuals affected with autosomal recessive Wilson disease (PMID: 25614872, 31611883), indicating that this variant contributes to disease. 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.

Nov 13, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Y2049D variant (also known as c.6145T>G), located in coding exon 41 of the ATM gene, results from a T to G substitution at nucleotide position 6145. The tyrosine at codon 2049 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This variant has been identified in individuals diagnosed with ataxia telangiectasia (Podralska MJ et al. Mol Genet Genomic Med. 2014 Nov;2:504-11; Maciejczyk M et al. Front Immunol, 2019 Sep;10:2322). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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.

Hereditary breast ovarian cancer syndrome Pathogenic:1

Jan 09, 2024

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

. According to the ACMG standard criteria we chose these criteria: PM2 (supporting pathogenic): Absent from controls , PM3 (strong pathogenic): found in trans in AT-patients: Maciejczyk et al und Podralska et al., PP3 (supporting pathogenic): REVEL: 0,83

not provided Uncertain:1

Oct 25, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted ATM c.6145T>G at the cDNA level, p.Tyr2049Asp (Y2049D) at the protein level,and results in the change of a Tyrosine to an Aspartic Acid (TAT>GAT). This variant was observed in the compoundheterozygous state with another ATM variant in a pediatric patient with ataxia-telangiectasia (Podralska 2014). ATMTyr2049Asp was not observed in large population cohorts (Lek 2016). Since Tyrosine and Aspartic Acid differ inpolarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATMTyr2049Asp occurs at a position that is conserved across species and is located within the FAT domain (Stracker2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based oncurrently available information, it is unclear whether ATM Tyr2049Asp is pathogenic or benign. We consider it to be avariant of uncertain significance

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.7
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.78		Loss of stability (P = 0.0156)
MVP		0.96
MPC		0.67
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.58
gMVP		0.89
Mutation Taster		=10/90	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: rs786203767; hg19: chr11-108186787;