11-108301655-G-C

Position:

chr11-108301655-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4BP6

The NM_000051.4(ATM):c.5185G>C(p.Val1729Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000899 in 1,613,474 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. V1729A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000088 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:14B:6

Conservation

PhyloP100: 2.78

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 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 0 benign, 17 uncertain in NM_000051.4

BP4

Computational evidence support a benign effect (MetaRNN=0.31675065).

BP6

Variant 11-108301655-G-C is Benign according to our data. Variant chr11-108301655-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127401.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=6}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.5185G>C	p.Val1729Leu	missense_variant	35/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.5185G>C	p.Val1729Leu	missense_variant	35/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000721

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000995

AC:

AN:

251144

Hom.:

AF XY:

0.0000958

AC XY:

AN XY:

135726

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.000123

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.0000876

AC:

128

AN:

1461358

Hom.:

Cov.:

AF XY:

0.0000949

AC XY:

AN XY:

726986

show subpopulations

Gnomad4 AFR exome

AF:

0.000389

Gnomad4 AMR exome

AF:

0.000380

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:

0.0000621

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.000112

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000721

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.000268

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:14Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:8

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 2023	Observed in individuals with ataxia-telangiectasia, including one individual who also carried a homozygous pathogenic ATM variant and another who carried a heterozygous ATM pathogenic variant on the opposite allele (in trans) (PMID: 17124347, 29482223, 33779842); Observed in individuals with breast, colorectal, uterine, and prostate cancer (PMID: 28640387, 29522266, 29684080, 30303537, 33436325, 35264596); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 11443540, 17124347, 22529920, 28640387, 29482223, 28652578, 29684080, 29522266, 19781682, 26689913, 30303537, 33203166, 33436325, 32522261, 35980532, 35264596, 37450374, 34482403, 33779842) -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The ATM p.Val1729Leu variant was identified in 3 of 9436 proband chromosomes (frequency: 0.0003) from individuals or families with cerebellar ataxia, Ataxia telangiectasia, and colorectal cancer, and was present in 2 of 4676 control chromosomes (frequency: 0.0004) from healthy individuals (Coutelier 2018, Magliozzi 2006, Ricker 2017, Tavtigian 2009, Thorstenson 2001). The variant was also identified in the following databases: dbSNP (ID: rs3092907) as "With Uncertain significance allele", ClinVar (1x likely benign, 3x uncertain significance), and Clinvitae. The variant was not identified in COGR, Cosmic, MutDB, LOVD 3.0, or ATM-LOVD. The variant was identified in control databases in 28 of 276848 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Other in 6 of 6458 chromosomes (freq: 0.0009), Latino in 6 of 34416 chromosomes (freq: 0.0002), and European in 16 of 126392 chromosomes (freq: 0.0001); it was not observed in the African, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. Multiple studies list this variant as a polymorphism and one study found this variant co-occurring with the ATM homozygous pathogenic variant c.9022C>T (p.R3008C) (Magliozzi 2006, Thorstenson 2001, Coutelier 2018), increasing the likelihood this variant may not have clinical significance. The p.Val1729 residue is not 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 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 20, 2020	The frequency of this variant in the general population, 0.00017 (6/35438 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with ataxia telangiectasia (AT) (PMID: 33779842 (2021), 17124347 (2006)) or cerebellar ataxia (PMID: 29482223 (2018)). It has also been reported in individuals with breast cancer (PMID: 33471991 (2021), 30303537 (2019), 29522266 (2018)), uterine cancer (PMID: 29684080 (2018)), prostate cancer (PMID: 33436325 (2021)), or colorectal cancer (PMID: 28640387 (2017)). This variant is also reported in individuals unaffected by cancer (PMID: 33471991 (2021), 28652578 (2017), FLOSSIES (http://whi.color.com/)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 20, 2020	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 28, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 04, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Mar 10, 2022	- -
Uncertain significance, no assertion criteria provided	clinical testing	True Health Diagnostics	Feb 23, 2018	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 08, 2021	- -

not specified

Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 14, 2022	DNA sequence analysis of the ATM gene demonstrated a sequence change, c.5185G>C, in exon 35 that results in an amino acid change, p.Val1729Leu. This sequence change has been described in the gnomAD database with a frequency of 0.017% in the Latino subpopulation (dbSNP rs3092907). The p.Val1729Leu change affects a moderately conserved amino acid residue located in a domain of the ATM protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Val1729Leu substitution. This sequence change has been reported in one individual with breast cancer (PMID: 30303537). It has also been detected in the homozygous state in one individual with a metabolic presentation ataxia (PMID: 29482223) and in trans with a pathogenic variant in a family with ataxia telangiectasia (PMID: 33779842). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Val1729Leu change remains unknown at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 27, 2023	Variant summary: ATM c.5185G>C (p.Val1729Leu) 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 0.0001 in 251330 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Ataxia-Telangiectasia (0.0001 vs 0.004), allowing no conclusion about variant significance. c.5185G>C has been reported in the literature as a "polymorphism" in a study of individuals affected with Ataxia-Telangiectasia, as a VUS in settings of multigene panel testing in an individual with a personal and/or family history of breast cancer and in unaffected controls (example, Magliozzi_2006, Tavtigian_2009, Pereira_2022). In one family the variant is reported to segregate with disease (example: Shalash_2021). However, these reports do not provide unequivocal conclusions about a penetrant association of the variant with Ataxia-Telangiectasia/ATM-related cancers. The following publications have been ascertained in the context of this evaluation (PMID: 22529920, 35264596, 33436325, 17124347, 35980532, 33779842, 19781682, 11443540). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (likely benign, n=4; VUS, n=8). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -

Familial cancer of breast

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 22, 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]. -

Ataxia-telangiectasia syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	Apr 09, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.098

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.090

T;T

Eigen

Benign

0.16

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.81

T;.

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.32

T;T

MetaSVM

Uncertain

-0.15

MutationAssessor

Uncertain

2.8

M;M

MutationTaster

Benign

0.93

D;D

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.3

N;N

REVEL

Uncertain

0.41

Sift

Uncertain

0.012

D;D

Sift4G

Uncertain

0.010

D;D

Polyphen

0.74

P;P

Vest4

0.47

MutPred

0.17

Loss of methylation at K1728 (P = 0.1413);Loss of methylation at K1728 (P = 0.1413);

MVP

0.90

MPC

0.17

ClinPred

0.19

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.33

gMVP

0.58

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