11-108345884-C-T

Variant names:

• chr11-108345884-C-T
• rs201958469
• NM_000051.4:c.8560C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PP3_Moderate BP6

The NM_000051.4(ATM):​c.8560C>T​(p.Arg2854Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00019 in 1,613,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2854L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:22 B:5 O:2
• Conservation: PhyloP100: 7.89
• Publications: 27 publications found

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]

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 46 uncertain in NM_000051.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937
• BP6: Variant 11-108345884-C-T is Benign according to our data. Variant chr11-108345884-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 142147.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.8560C>T	p.Arg2854Cys	missense_variant	Exon 58 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.8560C>T	p.Arg2854Cys	missense_variant	Exon 58 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000187 AC: 47 AN: 251070 AF XY: 0.000162

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000212

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000197 AC: 288 AN: 1461448 Hom.: 0 Cov.: 30 AF XY: 0.000198 AC XY: 144 AN XY: 727038

African (AFR) AF: 0.0000598 AC: 2 AN: 33456

American (AMR) AF: 0.000514 AC: 23 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86246

European-Finnish (FIN) AF: 0.000206 AC: 11 AN: 53414

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5760

European-Non Finnish (NFE) AF: 0.000206 AC: 229 AN: 1111740

Other (OTH) AF: 0.000298 AC: 18 AN: 60368

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152116 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74300

African (AFR) AF: 0.0000483 AC: 2 AN: 41416

American (AMR) AF: 0.000655 AC: 10 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000149 Hom.: 0

Bravo AF: 0.000117

ExAC AF: 0.000181 AC: 22

EpiCase AF: 0.0000546

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:22 Benign:5 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:9

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 08, 2022

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools predict that this variant is damaging. -

Mar 30, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 18, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ATM c.8560C>T (p.Arg2854Cys) variant has been reported in the published literature in individuals with breast cancer (PMID: 28779002 (2017), 30303537 (2019), 30613976 (2019), 32522261 (2020), 34646395 (2021), 34326862 (2021), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)), colorectal cancer (PMID: 26901136 (2016), 28135145 (2017), 30256826 (2018), 34326862 (2021)), chronic lymphocytic leukemia (PMID: 28652578 (2017)), and pancreatic cancer (PMID: 32113160 (2020)). This variant has also been found in reportedly healthy individuals (PMID: 28779002 (2017), 33471991 (2021), 36243179 (2022), 37262986 (2023)). The frequency of this variant in the general population, 0.00045 (16/35400 chromosomes in Admixed American 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 predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 30, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with a personal or family history of melanoma, breast, ovarian, colorectal, pancreatic, or other cancers (PMID: 19404735, 25186627, 26901136, 28779002, 28135145, 30256826, 30613976, 32113160, 31742824, 34262154, 34646395, 34326862, 36243179, 35534704, 37262986, 39251783); Published functional studies demonstrate no damaging effect: KAP1 phosphorylation similar to wild type (PMID: 40105422); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19404735, 25801821, 26901136, 28717660, 27043212, 28611190, 28135145, 28495793, 28779002, 29659569, 25186627, 30256826, 31159747, 30303537, 32113160, 31590326, 33054100, 33471991, 32522261, 26580448, 30613976, 28652578, 34646395, 31742824, 20305132, 34262154, 35534704, 36099812, 37436117, 23555315, 36243179, 35264596, 34326862, 23532176, 39590369, 37262986, 38633426, 39251783, 40105422) -

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATM: PP3 -

Hereditary cancer-predisposing syndrome Uncertain:4 Benign:1

Aug 01, 2018

GeneKor MSA

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 24, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with cysteine at codon 2854 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 individuals affected with breast cancer, colorectal cancer and prostate cancer (PMID: 19404735, 20305132, 23555315, 26901136, 28135145, 28779002, 29659569, 30256826, 34646395, 33471991, 35264596). This variant has also been identified in 49/282448 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. -

Dec 16, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Feb 26, 2024

Hereditary Cancer Laboratory, Hospital Universitario 12 de Octubre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM1+PM2+PP3 -

Familial cancer of breast Uncertain:3 Benign:1

Aug 02, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PM2 supporting, PP3 supporting -

Aug 07, 2017

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant in the ATM gene was identified in a female patient with breast cancer at 45 years, and a familial history of breast cancer: 2 maternal cousins, 2 maternal aunts, one maternal grand-mother and one paternal cousin. -

Jun 20, 2024

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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]. -

Mar 17, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast Uncertain:1 Other:1

-

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Uncertain significance and reported on 03-07-2016 by Lab Ambry Genetics. 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. -

Feb 18, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ataxia-telangiectasia syndrome Benign:2

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 23, 2025

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity. -

Astrocytoma IDH-mutant Uncertain:1

-

Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Carcinoma of colon Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATM p.Arg2854Cys variant was identified in 1 of 3258 proband chromosomes (frequency: 0.0003) from individuals or families with breast and/or ovarian cancer and tested negative for BRCA1 and BRCA2 (Paglia 2010). The variant was also identified in the following databases: dbSNP (ID: rs201958469) as “With Uncertain significance allele”, in ClinVar (5x, as uncertain significance by Ambry Genetics, GeneDx, EGL Genetics, Invitae, Color Genomics), and Clinvitae (4x, as uncertain significance by ClinVar, Invitae and EmvClass). The variant was not identified in Cosmic, MutDB, LOVD 3.0, or ATM-LOVD databases. The variant was identified in control databases in 50 of 276788 chromosomes at a frequency of 0.000181 in the following populations: “other” in 4 of 6456 chromosomes (freq. 0.00061), Latino in 16 of 34376 chromosomes (freq. 0.00046), European in 26 of 126370 chromosomes (freq. 0.0002), Finnish in 3 of 25782 chromosomes (freq. 0.00011), and South Asian in 1 of 30778 chromosomes (freq. 0.000032) (Genome Aggregation Consortium Feb 27, 2017). Although the p.Arg2854 residue is not conserved in mammals, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the arginine variant may impact the protein. The variant occurs outside of the splicing consensus sequence and 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. -

Breast and/or ovarian cancer Uncertain:1

Mar 13, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ATM-related disorder Uncertain:1

Jan 12, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATM c.8560C>T variant is predicted to result in the amino acid substitution p.Arg2854Cys. This variant was reported in two individuals with breast cancer (Paglia et al. 2009. PubMed ID: 19404735, Table 1; Girard et al. 2018. PubMed ID: 30303537, Table S3), four individuals with colorectal cancer (de Voer et al. 2016. PubMed ID: 26901136, Table S3; Yurgelun et al. 2017. PubMed ID: 28135145, Table A4), an individual with prostate cancer (Paulo et al. 2018. PubMed ID: 29659569, Table 2), and an individual undergoing hereditary cancer testing (Tsaousis et al. 2019. PubMed ID: 31159747, Table S5). It has also been observed in a case and multiple controls from a chronic lymphocytic leukemia cohort (Tiao et al. 2017. PubMed ID: 28652578, Table S6). At PreventionGenetics, this variant has been observed in an individual with a family history of cancer who harbored a BRIP1 nonsense variant (internal data). This variant is reported in 0.045% of alleles in individuals of Latino descent in gnomAD and is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142147/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Papillary thyroid carcinoma Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATM p.Arg2854Cys variant was identified in 1 of 3258 proband chromosomes (frequency: 0.0003) from individuals or families with breast and/or ovarian cancer and tested negative for BRCA1 and BRCA2 (Paglia 2010). The variant was also identified in the following databases: dbSNP (ID: rs201958469) as “With Uncertain significance allele”, in ClinVar (5x, as uncertain significance by Ambry Genetics, GeneDx, EGL Genetics, Invitae, Color Genomics), and Clinvitae (4x, as uncertain significance by ClinVar, Invitae and EmvClass). The variant was not identified in Cosmic, MutDB, LOVD 3.0, or ATM-LOVD databases. The variant was identified in control databases in 50 of 276788 chromosomes at a frequency of 0.000181 in the following populations: “other” in 4 of 6456 chromosomes (freq. 0.00061), Latino in 16 of 34376 chromosomes (freq. 0.00046), European in 26 of 126370 chromosomes (freq. 0.0002), Finnish in 3 of 25782 chromosomes (freq. 0.00011), and South Asian in 1 of 30778 chromosomes (freq. 0.000032) (Genome Aggregation Consortium Feb 27, 2017). Although the p.Arg2854 residue is not conserved in mammals, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the arginine variant may impact the protein. The variant occurs outside of the splicing consensus sequence and 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 specified Benign:1

Jan 27, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATM c.8560C>T (p.Arg2854Cys) results in a non-conservative amino acid change located in the Phosphatidylinositol 3-/4-kinase, catalytic domain (IPR000403) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 255074 control chromosomes, predominantly at a frequency of 0.00046 within the Latino subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (0.0002 vs 0.001), allowing no conclusion about variant significance. c.8560C>T has been reported in the literature in individuals affected with breast cancer, colorectal cancer, chronic lymphocytic leukemia, prostate cancer, Lynch syndrome and melanoma (e.g. LaPaglia_ 2009, Bernstein_2010, Tung_2014, deVoer2016, Yurgelun_2017, Tiao_2017, Paulo_2018, Martin-Morales_2018, Girard_2019, Rizzolo_2019, Tsaousis_2019, Velzquez_2020, Daimasso_2021). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrence with another pathogenic variant has been reported (CHEK2 c.1232G>A, p.W411*, internal data), providing supporting evidence for a benign role. In addition, this variant was found in one healthy older woman in a reputed germline gnomic database (FLOSSIES). 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: 19404735, 20305132, 25186627, 26901136, 28135145, 28717660, 26580448, 28652578, 30256826, 29659569, 30303537, 31159747, 30613976, 34262154, 32522261, 37262986). ClinVar contains an entry for this variant (Variation ID: 142147). Based on the evidence outlined above, the variant was classified as likely benign. -

Neoplasm Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: -

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.60	D;D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;.
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	0.57	D
MutationAssessor	Pathogenic	3.4	M;M
PhyloP100		7.9
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-6.4	D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.95
MutPred		0.81		Loss of disorder (P = 0.086);Loss of disorder (P = 0.086);
MVP		0.98
MPC		0.68
ClinPred		0.83	D
GERP RS		5.5
Varity_R		0.90
gMVP		0.84
Mutation Taster		=6/94	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs201958469; hg19: chr11-108216611; COSMIC: COSV53748690; COSMIC: COSV53748690;