rs149911447

Variant names:

• chr11-108272808-C-A
• rs149911447
• NM_000051.4:c.3240C>A

Your query was ambiguous. Multiple possible variants found:

• chr11-108272808-C-A
• chr11-108272808-C-G
• chr11-108272808-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1 BP4 BP6

The NM_000051.4(ATM):​c.3240C>A​(p.Asp1080Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,068 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. D1080Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:2
• Conservation: PhyloP100: 0.668
• Publications: 4 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 0 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 35 uncertain in NM_000051.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.3774053).
• BP6: Variant 11-108272808-C-A is Benign according to our data. Variant chr11-108272808-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 407683.

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.3240C>A	p.Asp1080Glu	missense	Exon 22 of 63	NP_000042.3
	ATM	NM_001351834.2		c.3240C>A	p.Asp1080Glu	missense	Exon 23 of 64	NP_001338763.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.3240C>A	p.Asp1080Glu	missense	Exon 22 of 63	ENSP00000501606.1
	ATM	ENST00000452508.7	TSL:1	c.3240C>A	p.Asp1080Glu	missense	Exon 23 of 64	ENSP00000388058.2
	ATM	ENST00000531525.3	TSL:1	c.3240C>A	p.Asp1080Glu	missense	Exon 22 of 30	ENSP00000434327.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251264 AF XY: 0.00

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461780 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727198

African (AFR) AF: 0.0000896 AC: 3 AN: 33474

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111970

Other (OTH) AF: 0.0000331 AC: 2 AN: 60390

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74458

African (AFR) AF: 0.0000481 AC: 2 AN: 41570

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000113

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ataxia-telangiectasia syndrome Uncertain:1 Benign:2

Jan 22, 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

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.

Hereditary cancer-predisposing syndrome Uncertain:2

Dec 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D1080E variant (also known as c.3240C>A), located in coding exon 21 of the ATM gene, results from a C to A substitution at nucleotide position 3240. The aspartic acid at codon 1080 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration has been reported in the germline of a male diagnosed with acute mega-karyoblastic leukemia and synchronous mediastinal germ cell tumor of common clonal origin at age 17 (Oshrine BR et al. Cancer Genet 2014 Apr; 207(4):153-9). This alteration has also been reported in a cohort of 488 patients with stages I to III breast cancer who were tested with a 25-gene panel test (Tung N et al. J. Clin. Oncol., 2016 May;34:1460-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Feb 20, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces aspartic acid with glutamic acid at codon 1080 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 26976419). This variant has been identified in 6/251264 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.

not specified Uncertain:1

Mar 21, 2021

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATM c.3240C>A (p.Asp1080Glu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251264 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3240C>A has been reported in the literature as a VUS in an individual with breast cancer (example, Tung_2016), a study cohort of individuals undergoing WES for neurodevelopmental disorders without a cancer diagnosis (example, Kraemer_2019), a male with acute megakaryoblastic leukemia and mediastinal germ cell tumor (example, Oshrine_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer/Ataxia Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

not provided Uncertain:1

Jan 15, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted ATM c.3240C>A at the cDNA level, p.Asp1080Glu (D1080E) at the protein level, and results in the change of an Aspartic Acid to a Glutamic Acid (GAC>GAA). This variant has been observed in at least one patient with breast cancer as well as in an individual with concurrent acute megakaryoblastic leukemia and a mediastinal germ cell tumor, and was absent from 400 control samples (Oshrine 2014, Tung 2016). ATM Asp1080Glu was observed at an allele frequency of 0.026% (4/15,300) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is located within the region of interaction with beta-adaptin (Tavtigian 2009). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Asp1080Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

Familial cancer of breast Uncertain:1

Mar 21, 2023

Baylor 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	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	0.11
Eigen_PC	Benign	0.032
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		0.67
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.60		Gain of helix (P = 0.062)
MVP		0.84
MPC		0.37
ClinPred		0.96	D
GERP RS		2.0
Varity_R		0.27
gMVP		0.46
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs149911447; hg19: chr11-108143535;