11-108310287-A-G

Position:

chr11-108310287-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_000051.4(ATM):c.5890A>G(p.Lys1964Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000756 in 1,613,438 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000073 ( 1 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13B:6

Conservation

PhyloP100: 6.73

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:

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_benign. Variant got -1 ACMG points.

BP6

Variant 11-108310287-A-G is Benign according to our data. Variant chr11-108310287-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 142126.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=11}. Variant chr11-108310287-A-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.5890A>G	p.Lys1964Glu	missense_variant	39/63	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.5890A>G	p.Lys1964Glu	missense_variant	39/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000996

AC:

AN:

251046

Hom.:

AF XY:

0.000133

AC XY:

AN XY:

135694

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.000654

GnomAD4 exome

AF:

0.0000732

AC:

107

AN:

1461258

Hom.:

Cov.:

AF XY:

0.0000757

AC XY:

AN XY:

726956

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000783

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000211

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:13Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2017	This variant is denoted ATM c.5890A>G at the cDNA level, p.Lys1964Glu (K1964E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAG>GAG). ATM Lys1964Glu has been observed in at least two individuals with breast and/or ovarian cancer, and was absent from unaffected controls (Thorstenson 2003, Tavtigian 2009, Goldgar 2011). This variant was also reported in an individual undergoing multigene cancer panel testing due to a history of a Lynch syndrome-related cancer and/or polyps (Yurgelun 2015). ATM Lys1964Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Lysine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Lys1964Glu occurs at a position where amino acids with properties similar to Lysine are tolerated across species and is located in the FAT domain (Stracker 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether ATM Lys1964Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 15, 2024	Variant summary: ATM c.5890A>G (p.Lys1964Glu) results in a conservative amino acid change located in the PIK-related kinase domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.8e-05 in 255536 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (9.8e-05 vs 0.001), allowing no conclusion about variant significance. c.5890A>G has been reported in the literature in individuals affected with different types of cancer or dysnotia (e.g.Tavtigian_2009, Yurgelun_2015, Pogoda_2019). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrence with a pathogenic variant has been reported (BRCA1 c.6302delA, p.Asn2101Metfs, Moradian_2021), 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: 21787400, 23555315, 33436325, 30651582, 33558524, 26837699, 29659569, 31920950, 19781682, 12810666, 31159747, 26787654, 25980754, 35264596). Based on the evidence outlined above, the variant was classified as VUS possibly benign. -

Ataxia-telangiectasia syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Sep 29, 2021	The ATM c.5890A>G (p.Lys1964Glu) missense change has a maximum frequency of 0.017% in gnomAD v2.1.1, including one individual homozygous for the variant (https://gnomad.broadinstitute.org/variant/11-108181014-A-G?dataset=gnomad_r2_1). This variant has been reported in individuals with hereditary breast and ovarian cancer (PMID: 12810666, 23555315, 28779002, 29522266, 31159747, 31206626, 32658311), endometrial cancer (PMID: 32885271), suspected Lynch syndrome (PMID: 25980754, 32885271), and dystonia (PMID: 31920950). A small case control study suggested that this variant is associated with breast cancer (PMID: 23555315), however other studies have observed this variant in relatively equal numbers of cases and controls (PMID: 31206626, 32658311). In addition, one individual with this variant is reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/variant/11-108181014-A-G). Six of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been observed in a case of pediatric AML in which the variant allele was lost in the tumor (internal data). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4. -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 28, 2023	This missense variant replaces lysine with glutamic acid at codon 1964 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 large international case-control study, this variant was reported in 12/60454 breast cancer cases and 13/53448 controls (OR=0.816, 95%CI 0.372 to 1.789, p-value=0.69; PMID: 33471991). This variant has been reported in other individuals affected with breast cancer (PMID: 19781682, 21787400, 23555315), ovarian cancer (PMID: 30651582, 36521553), suspected Lynch syndrome (PMID: 25980754), and advanced cancer (PMID: 28873162). This variant has been identified in 26/282432 chromosomes in the general population, including 1 homozygote, by the Genome Aggregation Database (gnomAD) and in an individual age 70 or older without cancer (https://whi.color.com/variant/11-108181014-A-G). 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. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 05, 2021	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. -

Familial cancer of breast

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 24, 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]. -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 29, 2022	- -

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

Jul 20, 2022

- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 23, 2017

- -

ATM-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 17, 2024

The ATM c.5890A>G variant is predicted to result in the amino acid substitution p.Lys1964Glu. This variant has been reported in individuals with breast/ovarian cancer (Thorstenson et al. 2003. PubMed ID: 12810666; Table S2, Tavtigian et al. 2009. PubMed ID: 19781682; Table A2, Krivokuca et al. 2019. PubMed ID: 30651582; Table S1, Moradian et al. 2021. PubMed ID: 33558524), prostate cancer (Table S3, Darst et al. 2021. PubMed ID: 32853339; Table S4, Karlsson et al. 2021. PubMed ID: 33436325), chronic lymphocytic leukemia (Table S8, Nadeu et al. 2016. PubMed ID: 26837699), and those undergoing Lynch syndrome testing (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754). In at least one individual a pathogenic variant was also identified in BRCA2 (Table S1, Moradian et al. 2021. PubMed ID: 33558524). This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD and has conflicting interpretations of pathogenicity of uncertain and likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142126/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Jul 14, 2023

1xhomozygot in gnomAD (others). According to the ACMG standard criteria we chose this criterium: BP4 (supporting benign): ClinGen Interpretation Guidelines for ATM Version 1.1: BP4 (REVEL score <.249) -

Endometrial carcinoma

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The ATM p.Lys1964Glu variant was identified in 4 of 13262 proband chromosomes (frequency: 0.0003) from individuals or families with breast cancer or Lynch syndrome and was not identified in 7630 control chromosomes from healthy individuals (Goldgar 2011, Tavtigian 2009, Thorstenson 2003, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs201963507 as "With Pathogenic, Uncertain significance allele"), ClinVar (1x as likely benign by Invitae and 5x as uncertain significance by Ambry Genetics, GeneDx, Color Genomics, Fulgent Genetics, and Integrated Genetics/Laboratory Corporation of America), and Cosmic (3x in Haematopoietic and lymphoid tissue). The variant was not identified in the COGR, MutDB, or LOVD 3.0 database. The variant was identified in control databases in 25 of 276812 chromosomes (1 homozygous) at a frequency of 0.00009 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24022 chromosomes (freq: 0.00004), Other in 2 of 6456 chromosomes (freq: 0.0003), Latino in 7 of 34384 chromosomes (1 homozygous, freq: 0.0002), European in 12 of 126464 chromosomes (freq: 0.0001), and South Asian in 3 of 30772 chromosomes (freq: 0.0001); it was not observed in the Ashkenazi Jewish, East Asian, or Finnish populations. The p.Lys1964 residue is not conserved in mammals and 4 of 5 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 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2024

ATM: BP4 -

Malignant tumor of breast

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Center of Medical Genetics and Primary Health Care

- -

Hereditary cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.058

T;T

Eigen

Benign

0.012

Eigen_PC

Benign

0.14

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.80

T;.

M_CAP

Pathogenic

0.51

MetaRNN

Uncertain

0.44

T;T

MetaSVM

Benign

-0.66

MutationAssessor

Uncertain

2.4

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.63

N;N

REVEL

Benign

0.21

Sift

Benign

0.29

T;T

Sift4G

Benign

0.22

T;T

Polyphen

0.053

B;B

Vest4

0.46

MutPred

0.55

Loss of methylation at K1964 (P = 0.0016);Loss of methylation at K1964 (P = 0.0016);

MVP

0.93

MPC

0.18

ClinPred

0.11

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.60

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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