11-108321385-T-G

Position:

chr11-108321385-T-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_000051.4(ATM):c.6537T>G(p.Ile2179Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,614,080 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:14B:2

Conservation

PhyloP100: 0.00

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:

ATM (HGNC:):

ATM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BP6

Variant 11-108321385-T-G is Benign according to our data. Variant chr11-108321385-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 186221.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=12}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.6537T>G	p.Ile2179Met	missense_variant	45/63	ENST00000675843.1	NP_000042.3	Q13315A0A024R3C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.6537T>G	p.Ile2179Met	missense_variant	45/63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000675

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251448

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.0000289

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:

0.0000171

AC:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

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:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000197

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.000675

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000777

Hom.:

Bravo

AF:

0.000261

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:14Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 15, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; Reported in a breast/prostate cancer case-control study, with no significant difference in frequency between cases and controls (PMID: 23555315); Observed in individuals with a personal and/or family history of breast cancer, as well as an individual with pheochromocytoma/paraganglioma (PMID: 25186627, 31206626, 35264596, 35980532, 36568162, 37529773); This variant is associated with the following publications: (PMID: 28093192, 25186627, 32832836, 31206626, 35264596, 35980532, 37529773, 36568162, 39324485, 23532176, 23555315) -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 19, 2023	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools disagree on the variant's effect on normal protein function. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 07, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 31, 2017	- -

Ataxia-telangiectasia syndrome

Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 2179 of the ATM protein (p.Ile2179Met). This variant is present in population databases (rs146243469, gnomAD 0.05%). This missense change has been observed in individual(s) with breast cancer (PMID: 25186627, 35264596). ClinVar contains an entry for this variant (Variation ID: 186221). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 10, 2024	The p.I2179M variant (also known as c.6537T>G), located in coding exon 44 of the ATM gene, results from a T to G substitution at nucleotide position 6537. The isoleucine at codon 2179 is replaced by methionine, an amino acid with highly similar properties. This variant has been reported in multiple individuals with features consistent with ATM-related cancer predisposition (Tung N et al. Cancer, 2015 Jan;121:25-33; Pereira JZ et al. Mol Biol Rep, 2022 Oct;49:9509-9520; Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190; van der Merwe NC et al. Front Oncol, 2022 Dec;12:938561). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Dec 23, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 15, 2020	- -

Familial cancer of breast

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jun 06, 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	Baylor Genetics	Mar 21, 2024	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 06, 2024

Variant summary: ATM c.6537T>G (p.Ile2179Met) results in a conservative amino acid change located in the FAT domain (IPR003151) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 150980 control chromosomes, predominantly at a frequency of 0.00068 within the African or African-American subpopulation in the gnomAD database (v3.1 genomes dataset). This frequency is somewhat lower than the estimated maximum expected for a pathogenic variant in ATM causing Breast Cancer (0.001), allowing no conclusion about variant significance. However, the variant was also reported in the FLOSSIES database in 7/2559 African American women (i.e. with an allele frequency of 0.001367), who were older than age 70 years who have never had cancer, suggesting that the variant is likely benign. c.6537T>G has been reported in the literature, predominately as a VUS in settings of multigene panel testing, in individuals affected with Breast Cancer or other tumor phenotype(s), who are primarily of Hispanic- or African ancestry, without strong evidence for causality (e.g. Haiman_2013, Tung_2014, Weitzel_2019, Pereira_2022, van der Merwe_2022, Guindalini_2022, Lima_2023). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. 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: 35264596, 23555315, 35980532, 25186627, 31206626, 36568162, 37529773). ClinVar contains an entry for this variant (Variation ID: 186221). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

ATM-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 19, 2024

The ATM c.6537T>G variant is predicted to result in the amino acid substitution p.Ile2179Met. This variant has been reported in an individual with breast cancer (Tung et al. 2015. PubMed ID: 25186627) and an individual with leiomyosarcoma (Lee et al. 2017. PubMed ID: 28093192). It was reported in a GWAS study of breast and prostate cancer risk in a multiethnic population (Haiman et al. 2013. PubMed ID: 23555315, Table S6.2). This variant is reported in 0.056% of alleles in individuals of African descent in gnomAD and is interpreted as uncertain significance by the vast majority of laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/186221/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, 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

0.10

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

T;T

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.89

D;.

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.60

D;D

MetaSVM

Benign

-0.36

MutationAssessor

Uncertain

2.4

M;M

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.4

N;N

REVEL

Uncertain

0.46

Sift

Uncertain

0.012

D;D

Sift4G

Uncertain

0.019

D;D

Polyphen

0.96

D;D

Vest4

0.69

MVP

0.81

MPC

0.46

ClinPred

0.33

GERP RS

-3.7

Varity_R

0.38

gMVP

0.31

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