rs141921797

Positions:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_000051.4(ATM):c.4082A>G(p.Gln1361Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000552 in 1,613,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:3

Conservation

PhyloP100: 5.58

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07235512).

BP6

Variant 11-108287688-A-G is Benign according to our data. Variant chr11-108287688-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 185234.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=9}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.4082A>G	p.Gln1361Arg	missense_variant	27/63	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.4082A>G	p.Gln1361Arg	missense_variant	27/63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000483

AC:

AN:

248700

Hom.:

AF XY:

0.0000446

AC XY:

AN XY:

134634

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.0000578

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000329

AC:

AN:

1461108

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

726880

show subpopulations

Gnomad4 AFR exome

AF:

0.00117

Gnomad4 AMR exome

AF:

0.0000671

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:

0.00

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.000269

AC:

AN:

152352

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.000986

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000708

Hom.:

Bravo

AF:

0.000249

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 25, 2022	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 1361 of the ATM protein (p.Gln1361Arg). This variant is present in population databases (rs141921797, gnomAD 0.06%). This missense change has been observed in individual(s) with colon cancer or melanoma (PMID: 29684080, 34262154). ClinVar contains an entry for this variant (Variation ID: 185234). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 30, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 21, 2024	Observed in individuals with melanoma, prostate, colorectal, breast, and renal cancer (PMID: 29684080, 34262154, 35264596, 36898365, 31206626); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23555315, 29684080, 31871109, 34262154, 35264596, 36898365, 39324485, 31206626) -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 21, 2023	- -

Familial cancer of breast

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jun 06, 2023	A variant of uncertain significance was detected in the ATM gene. This sequence change replaces glutamine with arginine at codon 1361 of the ATM protein (p.Gln1361Arg). This variant is present in population databases (rs141921797, ExAC 0.07%). This variant has been observed in individual(s) with breast cancer (PMID: 23555315). ClinVar contains an entry for this variant (Variation ID: 185234). In-silico predictions show benign computational verdict based on 9 benign predictions from PolyPhen, BayesDel_addAF, DEOGEN2, EIGEN, LIST-S2, MVP, MutationTaster, PrimateAI and SIFT vs 4 pathogenic predictions from DANN, FATHMM-MKL, M-CAP and MutationAssessor and the position is not highly conserved. Therefore, it has been classified as a Variant of Uncertain Significance. Heterozygous pathogenic/likely pathogenic mutations in ATM gene cause breast cancer susceptibility (OMIM#114480). -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Oct 13, 2022	The ATM c.4082A>G (p.Gln1361Arg) missense change has a maximum subpopulation frequency of 0.060% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant was reported in five individuals in a study of breast cancer, however it was not specified if the variant was found in cases or controls (PMID: 31871109). This variant is present in nine individuals in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 16, 2024	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 18, 2024	Variant summary: ATM c.4082A>G (p.Gln1361Arg) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 248700 control chromosomes, predominantly at a frequency of 0.00062 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (4.8e-05 vs 0.001), allowing no conclusion about variant significance In addition, this variant has also been reported in 4/7325 European American and 5/2559 African American (i.e. with an allele frequency of 0.000977) women who were older than age 70 and cancer free (in the FLOSSIES database). The variant, c.4082A>G, has also been reported in the literature in cohorts of individuals affected with various tumor phenotypes, but without providing information on the associated phenotypes (examples: Haiman_2013, Yehia_2018, Adedokun_2020 and Dalmasso_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. 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: 23555315, 29684080, 31871109, 34262154). ClinVar contains an entry for this variant (Variation ID: 185234). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 28, 2019	- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 22, 2022	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 26, 2022	This missense variant replaces glutamine with arginine at codon 1361 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. This variant has been reported in an individual affected with melanoma (PMID: 34262154) and five carriers in a breast cancer case-control study, however the cancer status of the carriers were not specified (PMID: 31871109). This variant also has been reported in 9 individuals age 70 years or older without cancer (FLOSSIES; https://whi.color.com/variant/11-108158415-A-G). This variant has been identified in 17/280106 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. -

ATM-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 08, 2024

The ATM c.4082A>G variant is predicted to result in the amino acid substitution p.Gln1361Arg. This variant was reported in several individuals with breast cancer (Table 5, Adedokun et al. 2020. PubMed ID: 31871109; Supp. Table 3, Guindalini et al. 2022. PubMed ID: 35264596; Table 3, Weitzel et al. 2019. PubMed ID: 31206626), in an individual with sporadic melanoma (Table S2, Dalmasso et al. 2021. PubMed ID: 34262154), and in an individual with Cowden syndrome (Table S9, Yehia et al. 2018. PubMed ID: 29684080). This variant is reported in 0.060% of alleles in individuals of African descent in gnomAD and is interpreted as a variant of uncertain significance by the vast majority of submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/185234/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.055

.;T;T;T

Eigen

Benign

0.039

Eigen_PC

Benign

0.14

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.55

T;T;.;T

M_CAP

Benign

0.027

MetaRNN

Benign

0.072

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

.;M;M;.

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.93

N;N;N;.

REVEL

Benign

0.14

Sift

Benign

0.063

T;T;T;.

Sift4G

Uncertain

0.027

D;T;T;T

Polyphen

0.012

.;B;B;.

Vest4

0.38, 0.40

MVP

0.85

MPC

0.14

ClinPred

0.076

GERP RS

5.8

Varity_R

0.089

gMVP

0.14

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

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