11-108365368-A-G

Position:

chr11-108365368-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BP4

The NM_000051.4(ATM):c.9031A>G(p.Met3011Val) variant causes a missense change. The variant allele was found at a frequency of 0.000039 in 1,614,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. M3011T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:1

Conservation

PhyloP100: 4.17

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 Uncertain_significance. Variant got 1 ACMG points.

PM1

In a helix (size 16) in uniprot entity ATM_HUMAN there are 9 pathogenic changes around while only 3 benign (75%) in NM_000051.4

BP4

Computational evidence support a benign effect (MetaRNN=0.3112887).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.9031A>G	p.Met3011Val	missense_variant	63/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.9031A>G	p.Met3011Val	missense_variant	63/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251442

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.00

Gnomad NFE exome

AF:

0.0000791

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000390

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000371

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000504

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000618

Hom.:

Bravo

AF:

0.0000756

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000412

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2023	Observed in individuals with a personal or family history of breast, prostate, or pancreatic cancer (PMID: 11505391, 12810666, 19781682, 33436325, 35047863); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 12810666, 11505391, 19781682, 26689913, 27200287, 25742471, 29641532, 30197789, 33436325, 35047863, 25148578, 23532176, 34482403, 37450374) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 11, 2017	The p.Met3011Val (rs372795527) has been reported in several individuals with breast carcinoma or a family history of breast cancer (Tavtigian, 2009; Teraoka, 2001; Thorstenson, 2003); however this variant has not been found associated with ataxia-telangiectasia nor primary immunodeficiency. This variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.004 percent (identified on 11 out of 277,168 chromosomes), and has been reported to the ClinVar database as a variant of unknown significance (VariationID: 181906). The methionine at position 3,011 is moderately conserved considering 9 species (Alamut v2.10) and computational analyses of the p.Met3011Val variant on protein structure and function indicate a neutral effect (SIFT: tolerated, GVGD: class C0, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Met3011Val variant with certainty. -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 09, 2021	- -

Familial cancer of breast

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Dec 28, 2022	The ATM c.9031A>G (p.Met3011Val) missense change has a maximum subpopulation frequency of 0.0077% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in individuals with a personal and/or family history of breast and/or cancer (PMID: 11505391, 12810666, 19781682). It is absent in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 28, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jun 24, 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

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 31, 2022	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3011 of the ATM protein (p.Met3011Val). This variant is present in population databases (rs372795527, gnomAD 0.008%). This missense change has been observed in individual(s) with breast cancer, glioblastoma multiforme and prostate cancer (PMID: 11505391, 12810666, 19781682, 26689913, 33436325). ClinVar contains an entry for this variant (Variation ID: 181906). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 06, 2020	- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 09, 2022	The p.M3011V variant (also known as c.9031A>G), located in coding exon 62 of the ATM gene, results from an A to G substitution at nucleotide position 9031. The methionine at codon 3011 is replaced by valine, an amino acid with highly similar properties. In one study, this alteration, which is located in the kinase domain, was found in 1 of 142 breast cancer cases diagnosed before age 45 and not in any of the 81 controls (Teraoka SN et al. Cancer. 2001 Aug;92(3):479-87). A second study found this alteration in 1 of 270 breast and/or ovarian cancer families (Thorstenson YR et al. Cancer Res. 2003 Jun;63(12):3325-33). Another study found this alteration in 2 of 4112 breast cancer cases and in 0 of 2399 controls pooled from multiple studies (Tavtigian SV et al. Am. J. Hum. Genet. 2009 Oct;85(4):427-46). This alteration was also reported in 1/5560 prostate cancer cases and in 0/3353 controls of European ancestry (Karlsson Q et al. Eur Urol Oncol, 2021 08;4:570-579). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 14, 2022	This missense variant replaces methionine with valine at codon 3011 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer or prostate cancer (PMID: 11505391, 19781682, 33436325). This variant has been identified in 11/282840 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 11, 2024

Variant summary: ATM c.9031A>G (p.Met3011Val) results in a conservative amino acid change located in the Phosphatidylinositol 3-/4-kinase, catalytic domain (IPR000403) 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 4e-05 in 251442 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (4e-05 vs 0.001), allowing no conclusion about variant significance. c.9031A>G has been reported in the literature in individuals in individuals affected with or without a family history of Breast Cancer (e.g. Tavtigian_2009, Teraoka_2001, Thorstenson_2003) and Prostate Cancer (e.g. Karlsson_2020). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (APC c.487C>T, p.Gln163Ter), providing supporting evidence for a benign role. 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: 27200287, 30197789, 33436325, 26689913, 25148578, 19781682, 11505391, 12810666). ClinVar contains an entry for this variant (Variation ID: 181906). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.091

T;T

Eigen

Benign

-0.054

Eigen_PC

Benign

0.073

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.89

D;.

M_CAP

Benign

0.019

MetaRNN

Benign

0.31

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.8

L;L

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.18

Sift

Benign

0.030

D;D

Sift4G

Uncertain

0.023

D;D

Polyphen

0.0050

B;B

Vest4

0.51

MVP

0.96

MPC

0.13

ClinPred

0.13

GERP RS

5.1

Varity_R

0.31

gMVP

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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