11-108289689-T-C

Variant names:

• chr11-108289689-T-C
• rs201666889
• NM_000051.4:c.4324T>C

Variant summary

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

The NM_000051.4(ATM):​c.4324T>C​(p.Tyr1442His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000391 in 1,613,474 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Y1442C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:19 B:8
• Conservation: PhyloP100: 7.75
• 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]

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 1 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 48 uncertain in NM_000051.4
• BP6: Variant 11-108289689-T-C is Benign according to our data. Variant chr11-108289689-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127385.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.4324T>C	p.Tyr1442His	missense_variant	Exon 29 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.4324T>C	p.Tyr1442His	missense_variant	Exon 29 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

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: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000327 AC: 82 AN: 250868 AF XY: 0.000273

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: 0.000277

Gnomad NFE exome AF: 0.000653

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000404 AC: 590 AN: 1461260 Hom.: 0 Cov.: 31 AF XY: 0.000376 AC XY: 273 AN XY: 726944

African (AFR) AF: 0.000120 AC: 4 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.000243 AC: 13 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5540

European-Non Finnish (NFE) AF: 0.000505 AC: 562 AN: 1111824

Other (OTH) AF: 0.000182 AC: 11 AN: 60338

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.000296 AC XY: 22 AN XY: 74374

African (AFR) AF: 0.0000724 AC: 3 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15280

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000544 AC: 37 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000537 Hom.: 3

Bravo AF: 0.000212

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000420 AC: 51

EpiCase AF: 0.000436

EpiControl AF: 0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:19 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:2

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 20, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATM: PM2, PP3 -

Aug 11, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in individuals with leukemia, breast, ovarian, and/or colorectal cancer, but also in unaffected controls (PMID: 17393301, 19781682, 22420423, 26689913, 27153395, 26976419, 28779002, 28652578, 29684080, 31882575); 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: 22420423, 26976419, 20346647, 17393301, 34326862, 19781682, 26420498, 24172824, 21787400, 26689913, 27153395, 27067391, 25479140, 20305132, 17623063, 28652578, 29684080, 30166531, 30197789, 30303537, 31882575, 33471991, 33359728, 28779002, 36029002, 30426508, 23555315, 34262154) -

Feb 08, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ataxia-telangiectasia syndrome Uncertain:4 Benign:1

Jun 15, 2017

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 31, 2025

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 22, 2022

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ATM c.4324T>C (p.Tyr1442His) missense change has a maximum frequency of 0.060% in gnomAD v2.1.1 ( https://gnomad.broadinstitute.org/variant/11-108160416-T-C ). Five of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in individuals with breast cancer (PMID: 17393301, 17623063, 19781682, 20346647, 22420423, 25186627, 26976419, 28779002, 29522266, 30303537, 31882575, 32885271, 34445631), Ewing sarcoma (PMID: 33332384), high grade glioma (PMID: 26580448), pancreatic cancer (PMID: 25479140), colorectal cancer (PMID: 29338072, 30166531), and chronic lymphocytic leukemia (PMID: 24172824, 28652578). Other studies have observed this variant in relatively equal numbers of cases and controls (PMID: 19781682, 28652578, 30303537). In addition, four individuals with this variant are reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/variant/11-108160416-T-C). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PP3. -

Apr 01, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast Uncertain:3 Benign:1

Jul 15, 2022

MGZ Medical Genetics Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 09, 2020

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 and/or ovarian cancer (Broecks 2008, Tavtigian 2009, Knappskog 2012, Lu 2015, Maxell 2016, Tung 2016). This variant has an overall allele frequency of 0.0003 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 17, 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]. -

Jun 27, 2024

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ATM c.4324T>C (p.Tyr1442His) missense change has a maximum frequency of 0.060% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in individuals with breast cancer (PMID: 17393301, 17623063, 19781682, 20346647, 22420423, 25186627, 26976419, 28779002, 29522266, 30303537, 31882575, 32885271, 34445631), Ewing sarcoma (PMID: 33332384), high grade glioma (PMID: 26580448), pancreatic cancer (PMID: 25479140), colorectal cancer (PMID: 29338072, 30166531), and chronic lymphocytic leukemia (PMID: 24172824, 28652578). Other studies have observed this variant in relatively equal numbers of cases and controls (PMID: 19781682, 28652578, 30303537). In addition, four individuals with this variant are reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/variant/11-108160416-T-C). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

not specified Uncertain:2 Benign:2

Jul 17, 2023

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.4324T>C (p.Tyr1442His) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 255904 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (0.00032 vs 0.001), allowing no conclusion about variant significance. c.4324T>C has been reported in the literature in individuals affected with Breast Cancer. However, a recent case-control study showed that this variant had higher allele frequency in controls than in cases (Dorling_2021), suggesting this variant is benign. Nineteen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=16) and benign/likely benign (n=3). 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

- -

Feb 17, 2020

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the ATM gene demonstrated a sequence change, c.4324T>C, in exon 29 that results in an amino acid change, p.Tyr1442His. The p.Tyr1442His change has been reported in individuals with breast cancer (PMID: 19781682, 27153395, 17393301, 22420423, 26976419, 26689913), as well as in a case-control study for chronic lymphocytic leukemia (PMID: 28652578). This sequence change has been described in the gnomAD database with a frequency of 0.061% in European populations (dbSNP rs201666889). The p.Tyr1442His change affects a highly conserved amino acid residue located in a domain of the ATM protein that is not known to be functional. The p.Tyr1442His substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to the lack of functional studies, the clinical significance of the p.Tyr1442His change remains unknown at this time. -

Aug 01, 2024

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

May 14, 2019

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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 10, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 26, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Breast and/or ovarian cancer Uncertain:1

Jun 21, 2022

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

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

- -

ATM-related disorder Uncertain:1

Mar 26, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATM c.4324T>C variant is predicted to result in the amino acid substitution p.Tyr1442His. This variant has been reported in patients with a personal or family history of breast or ovarian cancer as well as patients with chronic lymphocytic leukemia, but has also been reported in control individuals from the same studies (Table S2, Tavtigian et al. 2009. PubMed ID: 19781682; Broeks et al. 2007. PubMed ID: 17393301; Table S3, Girard et al. 2018. PubMed ID: 30303537; Knappskog et al. 2012. PubMed ID: 22420423; Table S5, Maxwell et al. 2016. PubMed ID: 27153395; Table S6, Tiao et al. 2017. PubMed ID: 28652578). This variant is reported in 0.061% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations in ClinVar of uncertain, likely benign, and benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/127385/). While we suspect 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. -

Malignant tumor of breast 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.Tyr1442His variant was identified in 7 of 11034 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer, and was not identified in 4798 control chromosomes from healthy individuals (Broeks 2008, Knappskog 2012, Maxwell 2016, Tavtigian 2009, Tung 2016). The variant was also identified in the following databases: dbSNP (ID: rs201666889) as With Uncertain significance allele, ClinVar (classified as uncertain significance by GeneDx, Invitae, Color Genomics and two clinical laboratories; classified as benign by Ambry Genetics), and LOVD 3.0 (VUS). The variant was not identified in the GeneInsight-COGR, Cosmic, or MutDB databases. The variant was identified in control databases in 82 of 276704 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Other in 1 of 6442 chromosomes (freq: 0.000155), European Non-Finnish in 76 of 126378 chromosomes (freq: 0.001), European Finnish in 5 of 25776 chromosomes (freq: 0.0002); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, and South Asian populations. The p.Tyr1442 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. 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. This variant was observed in one individual from our lab with a co-occurring pathogenic variant in CHEK2, c.1100delC, increasing the likelihood this variant does not have clinical significance. 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. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Nov 14, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

PP3, BS1. According to the ACMG standard criteria we chose these criteria: PP3 (supporting pathogenic): REVEL:0.733, BS1 (strong benign): Filtering Allele Frequency >.05%. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;D;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;.;D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.70	D;D;D
MetaSVM	Uncertain	0.030	D
MutationAssessor	Uncertain	2.9	M;M;.
PhyloP100		7.8
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-4.1	D;D;.
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.96
MVP		0.94
MPC		0.66
ClinPred		0.84	D
GERP RS		5.4
Varity_R		0.53
gMVP		0.74
Mutation Taster		=24/76	disease causing

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: rs201666889; hg19: chr11-108160416; COSMIC: COSV99069707;