11-108229287-A-G

Position:

chr11-108229287-A-G

Variant summary

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

The NM_000051.4(ATM):c.295A>G(p.Ser99Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000108 in 1,613,598 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00010 ( 1 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:8

Conservation

PhyloP100: 6.84

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:

ATM (HGNC:):

ATM 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=0.021582246).

BP6

Variant 11-108229287-A-G is Benign according to our data. Variant chr11-108229287-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127364.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=8, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.295A>G	p.Ser99Gly	missense_variant	4/63	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.295A>G	p.Ser99Gly	missense_variant	4/63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000459

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000287

AC:

AN:

250934

Hom.:

AF XY:

0.000280

AC XY:

AN XY:

135640

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000753

Gnomad ASJ exome

AF:

0.00377

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.000817

GnomAD4 exome

AF:

0.000101

AC:

147

AN:

1461440

Hom.:

Cov.:

AF XY:

0.0000853

AC XY:

AN XY:

727006

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000626

Gnomad4 ASJ exome

AF:

0.00325

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.000249

GnomAD4 genome

AF:

0.000177

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000459

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000957

Alfa

AF:

0.000345

Hom.:

Bravo

AF:

0.000208

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000181

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3472

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 26, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 07, 2022	Identified in patients with breast cancer, prostate cancer, or chronic lymphocytic leukemia, but also in healthy controls (Lahdesmaki 2004, Tavtigian 2009, Tung 2015, Decker 2017, Tiao 2017, Hauke 2018, Girard 2019, Karlsson 2021); 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: 30303537, 19781682, 14754616, 26787654, 28873162, 28652578, 28779002, 25186627, 29522266, 29684080, 31552911, 33436325) -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The ATM p.Ser99Gly variant was identified in 3 of 7786 proband chromosomes (frequency: 0.0004) from individuals or families with B-chronic lymphocytic leukemia or breast cancer and was not identified in 6732 control chromosomes from healthy individuals (LâˆšÂ§hdesmâˆšÂ§ki 2004, Tavtigian 2009, Young 2016). The variant was also identified in dbSNP (ID: rs137882485) as "With Uncertain significance allele" and ClinVar (classified as likely benign by Invitae; and as uncertain significance by Ambry Genetics, GeneDx, and five other submitters). The variant was not identified in the COGR, Cosmic, MutDB, or LOVD 3.0 databases. The variant was identified in control databases in 71 of 276750 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 39 of 10144 chromosomes (freq: 0.004), Other in 5 of 6464 chromosomes (freq: 0.0008), Latino in 23 of 34384 chromosomes (freq: 0.0007), and European in 4 of 126388 chromosomes (freq: 0.00003); it was not observed in the African, East Asian, Finnish, or South Asian populations. The p.Ser99 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. One study suggested a non-pathogenic role for this variant (LâˆšÂ§hdesmâˆšÂ§ki 2004). 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, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	ATM: PM2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 18, 2023	BS1 -

Ataxia-telangiectasia syndrome

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 17, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 29, 2021	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	Mar 05, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	True Health Diagnostics	Dec 01, 2017	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 12, 2021	- -

not specified

Uncertain:1Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 14, 2022	DNA sequence analysis of the ATM gene demonstrated a sequence change, c.295A>G, in exon 4 that results in an amino acid change, p.Ser99Gly. This sequence change has been described in the gnomAD database with a frequency of 0.38% in the Ashkenazi Jewish subpopulation (dbSNP rs137882485). The p.Ser99Gly change affects a highly 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.Ser99Gly substitution. The Ser99Gly change has been identified in individuals with breast cancer, prostate cancer, and chronic lymphocytic leukemia (PMID: 19781682, 33436325, 28652578). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Ser99Gly change remains unknown at this time. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 26, 2024	Variant summary: ATM c.295A>G (p.Ser99Gly) results in a non-conservative amino acid change located in the Telomere-length maintenance and DNA damage repair domain (IPR021668) 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 0.00011 in 1638634 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Ataxia-Telangiectasia (0.00011 vs 0.004), allowing no conclusion about variant significance. c.295A>G has been reported in the literature in individuals affected with Breast Cancer (examples: Tavtigian_2009, Tung_2015, Girard_2019), but also in healthy controls (examples: Tiao_2017, Girard_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer or Ataxia Telangiectasia. At-least two co-occurrences with other pathogenic variants have been observed in our laboratory (BRCA1 c.3481_3491delGAAGATACTAG, p.Glu1161fs; MSH2 c.942+3A>T), providing supporting evidence for a benign role. In addition, a recent case-control study showed that this variant was not associated with breast cancer (Dorling_2021). The following publications have been ascertained in the context of this evaluation (PMID: 19781682, 25186627, 14754616, 26787654, 28873162, 28652578, 30303537, 33471991, 30883245, 34262154, 35309086, 35264596, 33436325, 31206626). These report(s) do not provide unequivocal conclusions about association of the variant with ATM-related conditions. 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: 30883245, 34262154, 33471991, 35309086, 30303537, 35264596, 33436325, 14754616, 28873162, 19781682, 28652578, 25186627, 31206626, 26787654). ClinVar contains an entry for this variant (Variation ID: 127364). Based on the evidence outlined above, the variant was classified as likely benign. -

Familial cancer of breast

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 18, 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	Jul 01, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

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

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 04, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.070

.;T;T;.;T;T;T;T;T;T

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.80

T;T;T;T;.;.;.;.;.;T

M_CAP

Benign

0.079

MetaRNN

Benign

0.022

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.40

MutationAssessor

Uncertain

2.5

.;M;.;.;M;.;.;.;.;.

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.8

N;N;D;.;N;.;.;.;.;.

REVEL

Uncertain

0.30

Sift

Benign

0.050

D;T;T;.;T;.;.;.;.;.

Sift4G

Uncertain

0.057

T;T;T;T;T;.;.;.;T;T

Polyphen

1.0, 1.0

.;D;.;.;D;D;D;D;D;.

Vest4

0.36, 0.41, 0.46, 0.36

MVP

0.92

MPC

0.16

ClinPred

0.11

GERP RS

6.1

Varity_R

0.44

gMVP

0.33

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