rs879254132

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_000051.4(ATM):c.6680G>A(p.Arg2227His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,478 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2227C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 7.20

Variant links:

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]

ATM links:

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]

C11orf65 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-108325416-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.6680G>A	p.Arg2227His	missense_variant	46/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.6680G>A	p.Arg2227His	missense_variant	46/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251146

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135740

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461478

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727062

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 30, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2227 of the ATM protein (p.Arg2227His). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer (PMID: 31780696). ClinVar contains an entry for this variant (Variation ID: 246165). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATM protein function. This variant disrupts the p.Arg2227 amino acid residue in ATM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12552559, 15843990, 16380133, 18504682, 19691550, 22213089, 23264026, 23640770). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 13, 2020	- -

Hereditary cancer-predisposing syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 16, 2024	This missense variant replaces arginine with histidine at codon 2227 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 reported in an individual affected with breast cancer (PMID: 31780696). This variant has been identified in 1/251146 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same position (p.Arg2227Cys) is considered to be disease-causing (ClinVar variation ID: 33611), suggesting that arginine at this position is important for protein structure and function. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 04, 2022	The p.R2227H variant (also known as c.6680G>A), located in coding exon 45 of the ATM gene, results from a G to A substitution at nucleotide position 6680. The arginine at codon 2227 is replaced by histidine, an amino acid with highly similar properties. This alteration was identified in a cohort of breast cancer patients from Puerto Rico (Dutil J et al. Sci Rep, 2019 11;9:17769). Another amino acid substitution at this codon (p.R227C) has been identified in multiple individuals with ataxia-telangiectasia and associated with reduced protein levels and kinase activity compared to wild type ATM (Babaei M et al. Hum. Genet. 2005 Jul; 117(2-3):101-6; Buzin CH et al. Hum. Mutat. 2003 Feb; 21(2):123-31; Sandoval N et al. Hum. Mol. Genet. 1999 Jan; 8(1):69-79; Meissner G et al.Mov Disord. 2013 Nov;28(13):1897-9; Mitui M et al. Hum. Mutat. 2009 Jan; 30(1):12-21). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jul 13, 2021	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 13, 2020

Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in an individual with breast cancer (Dutil 2019); This variant is associated with the following publications: (PMID: 31780696, 12552559, 15843990, 16380133, 18504682, 19691550, 23264026, 23640770, 22213089) -

Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.35

T;T

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;.

M_CAP

Pathogenic

0.29

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

0.62

MutationAssessor

Uncertain

2.7

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-4.9

D;D

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;D

Vest4

0.88

MutPred

0.95

Gain of catalytic residue at L2226 (P = 0.107);Gain of catalytic residue at L2226 (P = 0.107);

MVP

0.97

MPC

0.65

ClinPred

1.0

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.72

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over