Variant rs758180727 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_000051.4(ATM):c.4247A>G(p.Gln1416Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000964 in 1,452,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 5.73

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:

ATM (HGNC:):

ATM links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.34123245).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.4247A>G	p.Gln1416Arg	missense_variant	29/63	ENST00000675843.1	NP_000042.3	Q13315A0A024R3C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.4247A>G	p.Gln1416Arg	missense_variant	29/63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000163

AC:

AN:

245772

Hom.:

AF XY:

0.0000150

AC XY:

AN XY:

133156

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:

0.0000358

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000964

AC:

AN:

1452548

Hom.:

Cov.:

AF XY:

0.00000831

AC XY:

AN XY:

721834

show subpopulations

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:

0.0000117

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 11, 2023	This missense variant replaces glutamine with arginine at codon 1416 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. In a case-control study, this variant was detected in 1/13087 breast cancer cases and absent in 5488 controls (PMID: 33471991). This variant has been identified in 4/245772 chromosomes 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 27, 2023	The p.Q1416R variant (also known as c.4247A>G), located in coding exon 28 of the ATM gene, results from an A to G substitution at nucleotide position 4247. The glutamine at codon 1416 is replaced by arginine, an amino acid with highly similar properties. This alteration was identified in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS ONE, 2018 Apr;13:e0194098). This alteration has also been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J. Med. Genet., 2017 11;54:732-741). This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Ataxia-telangiectasia syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 29, 2023

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 1416 of the ATM protein (p.Gln1416Arg). This variant is present in population databases (rs758180727, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 230064). 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 24, 2023

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; Observed in individual(s) with breast cancer (Decker et al., 2017); This variant is associated with the following publications: (PMID: 28779002, 29641532) -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The ATM p.Gln1416Arg variant was not identified in the literature nor was it identified in the LOVD 3.0, database. The variant was identified in dbSNP (ID: rs758180727) as "With Uncertain significance allele", and ClinVar (classified as uncertain significance by Invitae and Ambry Genetics). The variant was identified in control databases in 4 of 241304 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 4 of 109806 chromosomes (freq: 0.00004), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Gln1416 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Q variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Uncertain

0.027

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

T;T;T

Eigen

Benign

0.032

Eigen_PC

Benign

0.063

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

T;.;T

M_CAP

Benign

0.061

MetaRNN

Benign

0.34

T;T;T

MetaSVM

Benign

-0.64

MutationAssessor

Uncertain

2.8

M;M;.

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.2

D;D;.

REVEL

Uncertain

0.45

Sift

Uncertain

0.0050

D;D;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.98

D;D;.

Vest4

0.63

MutPred

0.38

Gain of phosphorylation at S1414 (P = 0.0765);Gain of phosphorylation at S1414 (P = 0.0765);.;

MVP

0.83

MPC

0.52

ClinPred

0.87

GERP RS

2.8

Varity_R

0.25

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

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