11-108316060-T-G

Position:

• chr11-108316060-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. 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).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:5
• Conservation: PhyloP100: 5.67

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]

ATM (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• 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 id is 187481.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=5, Likely_pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.6145T>G	p.Tyr2049Asp	missense_variant	42/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.6145T>G	p.Tyr2049Asp	missense_variant	42/63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 20, 2020	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 (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed as a heterozygous variant in an individual affected with ataxia-telangiectasia (PMID: 25614872). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 25, 2023	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 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. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Ataxia-telangiectasia syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 19, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 07, 2023	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). ClinVar contains an entry for this variant (Variation ID: 187481). 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. 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. -

Familial cancer of breast Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 26, 2024

- -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

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

Jan 09, 2024

. 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 specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 29, 2023

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 as a biallelic compound heterozygous genotype in at-least three 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). These data indicate that the variant may be associated with disease. 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). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 25, 2017

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 v4.3

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;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;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.6	M;M
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-7.0	D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.95
MutPred		0.78		Loss of stability (P = 0.0156);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs786203767; hg19: chr11-108186787;