11-108330219-C-T

Position:

chr11-108330219-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_000051.4(ATM):c.7313C>T(p.Thr2438Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00011 in 1,613,864 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).

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000068 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:9

Conservation

PhyloP100: 4.47

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:

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]

C11orf65 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.044849783).

BP6

Variant 11-108330219-C-T is Benign according to our data. Variant chr11-108330219-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127440.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=4, Likely_benign=7}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.7313C>T	p.Thr2438Ile	missense_variant	50/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.7313C>T	p.Thr2438Ile	missense_variant	50/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes

AF:

0.000512

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00171

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000147

AC:

AN:

250926

Hom.:

AF XY:

0.0000811

AC XY:

AN XY:

135626

show subpopulations

Gnomad AFR exome

AF:

0.00197

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000684

AC:

100

AN:

1461544

Hom.:

Cov.:

AF XY:

0.0000578

AC XY:

AN XY:

727094

show subpopulations

Gnomad4 AFR exome

AF:

0.00203

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.000506

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.000470

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00171

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000106

Hom.:

Bravo

AF:

0.000623

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000132

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 08, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Feb 14, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 11, 2019	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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jan 11, 2022	- -

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 22, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 05, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 17, 2021	This variant is associated with the following publications: (PMID: 17333338, 23274167, 33309985, 22529920, 8808599, 25503501, 10817650, 25980754, 19781682, 28779002, 23555315, 21933854, 30287823, 33095795) -

Ataxia-telangiectasia syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -

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, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 03, 2024

The ATM c.7313C>T variant is predicted to result in the amino acid substitution p.Thr2438Ile. This variant has been reported in an individual with ataxia telangiectasia but appeared to be in cis with a truncating variant (Li and Swift. 2000. PubMed ID: 10817650). This variant has been reported in an individual with suspected Lynch syndrome (Yurgelun et al. 2015. PubMed ID: 25980754, Supplemental table 2). One study reported that this variant is not associated with breast cancer (Haiman et al. 2013. PubMed ID: 23555315, Table S6). it has also been observed in three individuals with breast cancer (Table S3, Guindalini et al. 2022. PubMed ID: 35264596) and found in a control individual from a breast cancer study (Hirsch et al. 2008. PubMed ID: 17333338). This variant is reported in 0.20% of alleles in individuals of African descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127440/). Although we suspect that 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.Thr2438Ile variant was identified in 6 of 43,426 proband chromosomes (frequency: 0.0001) from individuals or families with ataxia telangiectasia, Lynch Syndrome, or breast cancer and was present in 4 of 58,628 control chromosomes (frequency: 0.00006) from healthy individuals (Momozawa 2018, Hirsch 2008, Decker 2017, Yurgelun 2015, Maxwell 2015). The variant was identified in dbSNP (rs147604227) as â€šÃ„Ãºwith uncertain significance, other alleleâ€šÃ„Ã¹, ClinVar (classified as uncertain significance by Integrated Genetics, GeneDx, Eurofins and 3 other submitters; as likely benign by Invitae and Ambry Genetics; and as benign by Color) and LOVD 3.0 (observed 3x). The variant was identified in control databases in 55 of 282,330 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 50 of 24,936 chromosomes (freq: 0.002) and Latino in 5 of 35,420 chromosomes (freq: 0.0001), while it was not observed in the Ashkenazi Jewish, East Asian, Finnish, European, Other or South Asian populations. The variant was observed in an ataxia telangiectasia patient in cis with a pathogenic ATM variant (Li 2000), decreasing the likelihood that this variant has clinical significance. The p.Thr2438 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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

Likely benign, criteria provided, single submitter

clinical testing

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

Jul 25, 2024

Variant summary: ATM c.7313C>T (p.Thr2438Ile) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain (IPR003151) of 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 0.00014 in 298578 control chromosomes, predominantly at a frequency of 0.002 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.7313C>T has been reported in the literature in sequencing studies of individuals with varied indications such as, an individual with Ataxia Telangiectasia (Li_2000), as not associated with risk of breast cancer in an array GWAS study of a multiethnic population (Haiman_2013), unaffected controls of African American and Japanese ancestry (Hirsch_2008, Momozawa_2018), a patient with a clinical indication of Lynch syndrome associated cancer and/or polyps undergoing multigene panel testing (Yurgelun_2015), and a patient with AML in the TGCA cohort (Lu_2015). Furthermore, the variant has been reported in a cerebellar ataxia patient (Coutelier_2018), breast cancer cases and controls (Weitzel_2019, Eygelaar_2022, Guindalini_2022), a patient with primary ovarian insufficiency (Franca_2020), in PDAC patients (Zimmermann_2021) and in Hepatic cancer cases and controls (Okawa_2023). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer or Ataxia Telangiectasia. Additionally, the variant was found to occur in ten African American women who are older than 70 years of age and cancer free as reported in the FLOSSIES database. 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: 29482223, 35039564, 33095795, 33309985, 35264596, 23555315, 17333338, 10817650, 26689913, 25503501, 30287823, 36243179, 21933854, 31206626, 33421217, 25980754, 33747920). ClinVar contains an entry for this variant (Variation ID: 127440). Based on the evidence outlined above, the variant was classified as likely benign. -

Familial cancer of breast

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Jun 13, 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]. -

Hereditary breast ovarian cancer syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.080

T;T

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

D;.

M_CAP

Benign

0.061

MetaRNN

Benign

0.045

T;T

MetaSVM

Benign

-0.42

MutationAssessor

Uncertain

2.3

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-1.3

N;N

REVEL

Uncertain

0.39

Sift

Benign

0.57

T;T

Sift4G

Benign

0.60

T;T

Polyphen

0.85

P;P

Vest4

0.52

MVP

0.88

MPC

0.41

ClinPred

0.033

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.35

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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