chr11-108271074-T-G

Variant names:

• chr11-108271074-T-G
• rs786203054
• NM_000051.4:c.2849T>G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_Strong PP5_Very_Strong

The NM_000051.4(ATM):​c.2849T>G​(p.Leu950Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000144 in 1,461,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 6.12

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965
• PP5: Variant 11-108271074-T-G is Pathogenic according to our data. Variant chr11-108271074-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 186574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.2849T>G	p.Leu950Arg	missense_variant	Exon 19 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.2849T>G	p.Leu950Arg	missense_variant	Exon 19 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461664 Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11 AN XY: 727156

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Pathogenic:3

May 06, 2019

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 950 of the ATM protein (p.Leu950Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with lymphoma, pancreatic cancer and ataxia-telangiectasia, and/or prostate cancer (PMID: 10873394, 12552559, 20678261, 21792198, 27989354, 28873162, 36346689). ClinVar contains an entry for this variant (Variation ID: 186574). 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. Experimental studies have shown that this missense change affects ATM function (PMID: 10873394, 20678261). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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. -

Nov 29, 2024

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.2849T>G (p.Leu950Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251366 control chromosomes (gnomAD). c.2849T>G has been reported in the literature in individuals affected with Ataxia-Telangiectasia (examples: Buzin_2003, Reiman_2011, Fang_2010, Thompson_2005) and other ATM-related cancers (example: Na_2017). These data indicate that the variant is likely to be associated with disease. Functional studies reveal that the variant affect ATM function (example: Fang_2010). The following publications have been ascertained in the context of this evaluation (PMID: 10873394, 12552559, 20678261, 27989354, 15928302, 21792198). ClinVar contains an entry for this variant (Variation ID: 186574). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Familial cancer of breast Pathogenic:2

Feb 06, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 23, 2024

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 10873394, 21792198, 20678261]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 10873394, 21792198, 12552559, 20678261]. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Jul 10, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L950R variant (also known as c.2849T>G), located in coding exon 18 of the ATM gene, results from a T to G substitution at nucleotide position 2849. The leucine at codon 950 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in multiple individuals diagnosed with ataxia telangiectasia (Becker-Catania SG et al. Mol. Genet. Metab. 2000 Jun;70:122-33; Buzin CH et al. Hum. Mutat. 2003 Feb;21:123-31; Reiman A et al. Br. J. Cancer 2011 Aug;105(4):586-91). This alteration was reported in a patient diagnosed with breast cancer as well as patient with localized prostate cancer (Yadav S et al. J Clin Oncol. 2020 05;38:1409-1418; Na R et al. Eur. Urol. 2017 May;71:740-747). Two studies have demonstrated that this alteration leads to lack of ATM protein expression (Becker-Catania SG et al. Mol. Genet. Metab. 2000 Jun;70:122-33; Fang Z et al. Genome Integr. 2010 Jun;1:9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Apr 07, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces leucine with arginine at codon 950 in the beta-adaptin interaction domain 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 reported in individuals affected with ataxia telangiectasia (PMID: 10873394, 12552559, 20678261, 21792198), breast cancer (Color internal data), and prostate cancer (PMID: 27989354). 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. -

not provided Pathogenic:1

Jun 27, 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; This variant is associated with the following publications: (PMID: 21792198, 10330348, 30128536, 10873394, 20678261, 15928302, 27989354, 27304073, 28873162, 19781682, 34771661, 27535533, 32125938, 12552559, 36346689) -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Other:1

-

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Likely pathogenic and reported on 03-14-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	.;T;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;D;.
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Uncertain	2.9	.;M;M
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0020	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.98, 0.99
MutPred		0.82		Gain of disorder (P = 0.0348);Gain of disorder (P = 0.0348);Gain of disorder (P = 0.0348);
MVP		0.99
MPC		0.70
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.77
gMVP		0.78

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: rs786203054; hg19: chr11-108141801;