11-108289689-T-C

Position:

chr11-108289689-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BP6

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:16B:8

Conservation

PhyloP100: 7.75

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 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, 16 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 id is 127385.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=15, Likely_benign=6, Benign=2}. Variant chr11-108289689-T-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.4324T>C	p.Tyr1442His	missense_variant	29/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.4324T>C	p.Tyr1442His	missense_variant	29/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000269

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.000327

AC:

AN:

250868

Hom.:

AF XY:

0.000273

AC XY:

AN XY:

135624

show subpopulations

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 SAS 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.:

Cov.:

AF XY:

0.000376

AC XY:

273

AN XY:

726944

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000243

Gnomad4 NFE exome

AF:

0.000505

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000269

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000544

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000513

Hom.:

Bravo

AF:

0.000212

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000420

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:16Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:3

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 20, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2023	Observed in individuals with leukemia, breast, ovarian, and/or colorectal cancer, but also in unaffected controls (Broeks et al., 2008; Tavtigian et al., 2009; Knappskog et al., 2012; Lu et al., 2015; Maxwell et al., 2016; Tung et al., 2016; Decker et al., 2017; Tiaoet al., 2017; Yehia et al., 2018; Jarhelle et al., 2019); 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, 19781682, 26420498, 24172824, 21787400, 23555315, 26689913, 27153395, 27067391, 25479140, 20305132, 17623063, 28652578, 29684080, 30166531, 30197789, 30303537, 31882575, 33471991, 33359728, 28779002, 36029002, 30426508) -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 08, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 08, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	ATM: PM2, PP3 -

Ataxia-telangiectasia syndrome

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jun 15, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Jan 22, 2022	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 01, 2022	- -

not specified

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 17, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 17, 2020	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. -

Familial cancer of breast

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 17, 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	Jul 15, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Division of Medical Genetics, University of Washington	Apr 09, 2020	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 -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 14, 2019	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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 10, 2020	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Oct 26, 2021	- -

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

Jun 21, 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, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 21, 2023

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 (http://gnomad.broadinstitute.org/variant/11-108160416-T-C) 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

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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

Uncertain significance, criteria provided, single submitter

curation

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

Nov 14, 2023

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

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

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

LIST_S2

Uncertain

0.90

D;.;D

M_CAP

Uncertain

0.24

MetaRNN

Uncertain

0.70

D;D;D

MetaSVM

Uncertain

0.030

MutationAssessor

Uncertain

2.9

M;M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.80

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

GERP RS

5.4

Varity_R

0.53

gMVP

0.74

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

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