11-108293469-C-T

Variant names:

• chr11-108293469-C-T
• rs35962982
• NM_000051.4:c.4768C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1 PP3 BP6

The NM_000051.4(ATM):​c.4768C>T​(p.Leu1590Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000127 in 1,610,480 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic 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. L1590R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:5
• Conservation: PhyloP100: 5.11
• Publications: 14 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]

ATM Gene-Disease associations (from GenCC):

• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
• ataxia telangiectasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• familial ovarian cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• gastric carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 30 uncertain in NM_000051.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.799
• BP6: Variant 11-108293469-C-T is Benign according to our data. Variant chr11-108293469-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 181961.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000051.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	NM_000051.4	MANE Select	c.4768C>T	p.Leu1590Phe	missense	Exon 31 of 63	NP_000042.3
	ATM	NM_001351834.2		c.4768C>T	p.Leu1590Phe	missense	Exon 32 of 64	NP_001338763.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.4768C>T	p.Leu1590Phe	missense	Exon 31 of 63	ENSP00000501606.1
	ATM	ENST00000452508.7	TSL:1	c.4768C>T	p.Leu1590Phe	missense	Exon 32 of 64	ENSP00000388058.2
	ATM	ENST00000531525.3	TSL:1	c.4437-1458C>T		intron	N/A	ENSP00000434327.3

Frequencies

GnomAD3 genomes AF: 0.000178 AC: 27 AN: 152084 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000128 AC: 32 AN: 250352 AF XY: 0.000111

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 FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.000247

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000122 AC: 178 AN: 1458396 Hom.: 1 Cov.: 30 AF XY: 0.000123 AC XY: 89 AN XY: 725732

African (AFR) AF: 0.00 AC: 0 AN: 33386

American (AMR) AF: 0.00 AC: 0 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39516

South Asian (SAS) AF: 0.00 AC: 0 AN: 86130

European-Finnish (FIN) AF: 0.000169 AC: 9 AN: 53188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5664

European-Non Finnish (NFE) AF: 0.000146 AC: 162 AN: 1109516

Other (OTH) AF: 0.000116 AC: 7 AN: 60242

GnomAD4 genome AF: 0.000178 AC: 27 AN: 152084 Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 10 AN XY: 74282

African (AFR) AF: 0.00 AC: 0 AN: 41402

American (AMR) AF: 0.00 AC: 0 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10578

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

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000310 Hom.: 0

Bravo AF: 0.0000604

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.000327

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:2

Sep 16, 2024

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant NM_000051.4(ATM):c.4768C>T (p.Leu1590Phe) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. There is a small physicochemical difference between leucine and phenylalanine, which is not likely to impact secondary protein structure as these residues share similar properties. The gene ATM has a low rate of benign missense variation as indicated by a high missense variants Z-Score of 2.52. The gene ATM contains 167 pathogenic missense variants, indicating that missense variants are a common mechanism of disease in this gene. 2 variants within 6 amino acid positions of the variant p.Leu1590Phe have been shown to be pathogenic, while none have been shown to be benign. The p.Leu1590Phe missense variant is predicted to be damaging by both SIFT and PolyPhen2. The leucine residue at codon 1590 of ATM is conserved in all mammalian species. The nucleotide c.4768 in ATM is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance

Sep 24, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

Apr 21, 2020

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.

Oct 26, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:3

Oct 26, 2017

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 19, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast or colorectal cancer and also in healthy controls (PMID: 25186627, 27978560, 28652578, 28135145, 29785153, 29522266, 29641532, 29684080, 33471991, 37239058); This variant is associated with the following publications: (PMID: 22529920, 27978560, 28135145, 26517685, 28652578, 29785153, 29522266, 29684080, 25186627, 29641532, 26193622, 27720647, 31422574, 33471991, 37239058)

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ataxia-telangiectasia syndrome Uncertain:2 Benign:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

May 21, 2018

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Familial cancer of breast Uncertain:2 Benign:1

Nov 12, 2019

Division of Medical Genetics, University of Washington

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported in the literature in individuals with breast cancer and colon cancer (Yurgelun 2017, Pearlman 2017, Goidescu 2018). This variant has an overall allele frequency of 0.0002 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved residue. Thus, it is unknown at this time whether this variant increases cancer risk. PP3

May 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].

Jul 06, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Uncertain:1 Benign:1

Aug 01, 2024

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.4768C>T (p.Leu1590Phe) results in a non-conservative amino acid change in 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 0.00013 in 1610480 control chromosomes, predominantly at a frequency of 0.00016 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (0.00013 vs 0.001), allowing no conclusion about variant significance. c.4768C>T has been reported in the literature in individuals affected with breast cancer (e.g. Tung_2015, Goidescu_2018, Catana_2023), prostate cancer (e.g. Karlsson_2021) and other types of cancer (e.g. Jori_2015, Pearlman_2016, Yurgelun_2017, Dalmasso_2021) as well as in healthy control individuals (e.g. Karlsson_2021 Dalmasso_2021). In addition, a case-control study showed that this variant is not associated with breast cancer (Dorling_2021). Co-occurrences with other pathogenic variants have been reported (BRCA1 c.181T>G, p.Cys61Gly (internal data); CHEK2 c.1283C>T, p.Ser428Phe (Goidescu_2018)), 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: 37239058, 34262154, 22529920, 29785153, 26517685, 33436325, 27978560, 25186627, 28135145). ClinVar contains an entry for this variant (Variation ID: 181961). Based on the evidence outlined above, the variant was classified as likely benign.

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 23, 2017

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	0.029	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.1
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.85
MVP		0.95
MPC		0.61
ClinPred		0.88	D
GERP RS		5.3
Varity_R		0.47
gMVP		0.54
Mutation Taster		=25/75	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35962982; hg19: chr11-108164196;