rs147600485

Positions:

chr11-108287672-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_000051.4(ATM):c.4066A>G(p.Asn1356Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000377 in 1,613,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00040 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:8O:1

Conservation

PhyloP100: -0.163

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.029222399).

BP6

Variant 11-108287672-A-G is Benign according to our data. Variant chr11-108287672-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127380.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Uncertain_significance=7, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.4066A>G	p.Asn1356Asp	missense_variant	27/63	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.4066A>G	p.Asn1356Asp	missense_variant	27/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.000279

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000137

AC:

AN:

248760

Hom.:

AF XY:

0.000149

AC XY:

AN XY:

134658

show subpopulations

Gnomad AFR exome

AF:

0.000123

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:

0.000288

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000402

AC:

588

AN:

1461560

Hom.:

Cov.:

AF XY:

0.000386

AC XY:

281

AN XY:

727086

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.0000224

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:

0.000498

Gnomad4 OTH exome

AF:

0.000447

GnomAD4 genome

AF:

0.000138

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0000481

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:

0.000279

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000300

Hom.:

Bravo

AF:

0.000132

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:8Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 16, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 28, 2019	The ATM c.4066A>G; p.Asn1356Asp variant (rs147600485) is reported in the literature in individuals with breast cancer (Sommer 2003, Tavtigian 2009, Tung 2015), and Lynch syndrome (Yurgelun 2015); however, this variant co-occurred with a pathogenic MSH2 deletion of exons 8-15 (Yurgelun 2015). This variant is also reported in ClinVar (Variation ID: 127380). It is found in the general population with an overall allele frequency of 0.01% (39/280160 alleles) in the Genome Aggregation Database. The asparagine at codon 1356 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Sommer SS et al. ATM missense mutations are frequent in patients with breast cancer. Cancer Genet Cytogenet. 2003 Sep;145(2):115-20. Tavtigian SV et al. Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer. Am J Hum Genet. 2009 Oct;85(4):427-46. Tung N et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer. 2015 Jan 1;121(1):25-33. Yurgelun MB et al. Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. Gastroenterology. 2015 Sep;149(3):604-13.e20. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 21, 2023	In the published literature, this variant has been reported in individuals with breast cancer (PMIDs: 33471991 (2021); LOVD3 Shared (https://databases.lovd.nl/shared/), 30938815 (2019), 28779002 (2017), 26898890 (2016), 19781682 (2009), and 12935922 (2003)), pancreatic cancer (PMID: 35047863 (2022)), and melanoma (PMID: 34262154 (2021)). The variant has also been reported in unaffected individuals (PMIDs: 35047863 (2022), 33471991 (2021); LOVD3 Shared (https://databases.lovd.nl/shared/), 28779002 (2017), 19781682 (2009), and FLOSSIES database (https://whi.color.com/)). In an individual undergoing multigene panel testing for suspected Lynch syndrome, this variant was reported to co-occur with a pathogenic variant in the MSH2 gene (PMID: 25980754 (2015)). The frequency of this variant in the general population, 0.00041 (20/48670 chromosomes in North-Western European subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	ATM: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 04, 2022	See Variant Classification Assertion Criteria. -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 26, 2020	- -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jun 24, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 30, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 23, 2016	- -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 21, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 15, 2023	Variant summary: ATM c.4066A>G (p.Asn1356Asp) results in a conservative amino acid change located in the Armadillo-type fold domain of 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 0.00014 in 248760 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (0.00014 vs 0.001), allowing no conclusion about variant significance. c.4066A>G has been reported in the literature as a VUS in settings of multigene panel testing in individuals affected with and/or undergoing testing for various types Cancer (example, Yurgelun_2015, Goldgar_2011, Sommer_2003, Tavtigian_2009, Caminsky_2016, Decker_2017, Lu_2015, Tung_2015, Oleary_20019, Dalmasso_2021, Dorling_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer/Ataxia-Telangiectasia. At-least two co-occurrences with other pathogenic variant(s) have been reported in the literature and at our laboratory (Yurgelun_2015, MSH2 del exons 8-15; Our laboratory, BRCA2 c.5350_5351delAA , p.Asn1784HisfsX2), providing supporting evidence for a benign role. 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: 26898890, 34262154, 28779002, 33471991, 21787400, 26689913, 30938815, 12935922, 19781682, 25186627, 25980754). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (Likely benign, n=5; VUS, n=7). Based on the evidence outlined above, the variant was classified as likely benign. -

Ataxia-telangiectasia syndrome

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Breast and/or ovarian cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Nov 08, 2022

- -

ATM-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 12, 2024

The ATM c.4066A>G variant is predicted to result in the amino acid substitution p.Asn1356Asp. This variant has been identified in individuals with breast cancer (Sommer et al. 2003. PubMed ID: 12935922; Tavtigian et al. 2009. PubMed ID: 19781682; Table S1, Goldgar et al. 2011. PubMed ID: 21787400; Table S2, Cohort 1 VUS, Tung et al. 2015. PubMed ID: 25186627; Table S14, Caminsky et al. 2016. PubMed ID: 26898890; Table S5, Decker et al. 2017. PubMed ID: 28779002), head, neck, squamous cell carcinoma (HNSC) (Table S12, Lu et al. 2015. PubMed ID: 26689913), and advanced cancer of unspecified type (eTable, Mendelker et al. 2017. PubMed ID: 28873162). It was also identified in an individual suspected of having Lynch syndrome, who also had a pathogenic variant in MSH2 (Table 2, Yurgelun et al. 2015. PubMed ID: 25980754). This variant is reported in 0.028% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127380/). This variant is located in the ARM repeat region, where multiple variant of unknown significance have been identified in patients (Yu et al. 2022. PubMed ID: 35047863). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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.Asn1356Asp variant was identified in 5 of 12902 proband chromosomes (frequency: 0.0004) from individuals or families with breast cancer or Lynch syndrome and was not identified in 7566 control chromosomes from healthy individuals (Sommer 2003, Goldgar 2011, Tavtigian 2009, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs147600485) as "With Uncertain significance allele", ClinVar (classified as likely benign by Ambry Genetics; and as uncertain significance by Invitae, GeneDx and three other submitters). The variant was not identified in LOVD 3.0 database. The variant was identified in control databases in 36 of 274476 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 3 of 24030 chromosomes (freq: 0.0001) and European in 33 of 124140 chromosomes (freq: 0.0003), while the variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Asn1356 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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

Benign:1

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]. -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

Variant interpreted as Likely benign and reported on 10-31-2019 by 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

Benign

0.063

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.61

CADD

Benign

1.2

DANN

Benign

0.31

DEOGEN2

Benign

0.068

.;T;T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.061

LIST_S2

Benign

0.54

T;T;.;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.029

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.075

.;N;N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.040

N;N;N;.

REVEL

Benign

0.12

Sift

Benign

0.89

T;T;T;.

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0

.;B;B;.

Vest4

0.33, 0.65

MVP

0.56

MPC

0.14

ClinPred

0.0036

GERP RS

-0.80

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.066

gMVP

0.090

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