11-108310218-G-C

Position:

chr11-108310218-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1

The NM_000051.4(ATM):c.5821G>C(p.Val1941Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000254 in 1,613,470 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V1941G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:16B:5

Conservation

PhyloP100: 7.27

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 2 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_000051.4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4 linkuse as main transcript	c.5821G>C	p.Val1941Leu	missense_variant	39/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1 linkuse as main transcript	c.5821G>C	p.Val1941Leu	missense_variant	39/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000368

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000131

AC:

AN:

251056

Hom.:

AF XY:

0.000133

AC XY:

AN XY:

135724

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

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:

0.000255

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000263

AC:

384

AN:

1461358

Hom.:

Cov.:

AF XY:

0.000245

AC XY:

178

AN XY:

727002

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

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:

0.000321

Gnomad4 OTH exome

AF:

0.000398

GnomAD4 genome

AF:

0.000171

AC:

AN:

152112

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000368

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000263

Hom.:

Bravo

AF:

0.000117

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:16Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 21, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16014569, 19781682, 21787400, 16832357, 21933854, 25503501, 25980754, 26580448, 25925381, 28971906, 29909963, 29522266, 25186627, 28779002, 28652578, 31843900, 9764584, 33471991, 33436325, 19431188, 35980532, 35534704, 34326862, 34262154) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ATM: PS3:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 05, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 11, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 21, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 18, 2016	- -

Hereditary cancer-predisposing syndrome

Pathogenic:1Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 01, 2024	The p.V1941L variant (also known as c.5821G>C), located in coding exon 38 of the ATM gene, results from a G to C substitution at nucleotide position 5821. The valine at codon 1941 is replaced by leucine, an amino acid with highly similar properties. One functional analysis of this variant showed an associated reduction, but not absence, of ATM kinase activity (Barone G et al. Hum. Mutat. 2009 Aug;30:1222-30). Across numerous studies, this alteration has been observed in multiple cancer cohorts and control groups (Tavtigian SV et al. Am. J. Hum. Genet. 2009 Oct;85:427-46; Skowronska A et al. Haematologica. 2012 Jan;97:142-6; Tung N et al. Cancer. 2015 Jan;121:25-33; Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346; Decker B et al. J Med Genet. 2017 11;54:732-741; Hauke J et al. Cancer Med. 2018 04;7:1349-1358; Karlsson Q et al. Eur Urol Oncol, 2021 Aug;4:570-579). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 19, 2021	- -
Likely pathogenic, flagged submission	research	Academic Department of Medical Genetics, University of Cambridge	Jan 26, 2018	Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Dec 07, 2021	- -

Ataxia-telangiectasia syndrome

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 16, 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 10, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -

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	May 23, 2023	The ATM c.5821G>C (p.Val1941Leu) missense change has a maximum subpopulation frequency of 0.025% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function. A functional study has shown reduced ATM protein level and kinase activity (PMID: 19431188). This variant has been identified in individuals with breast cancer (PMID: 16832357, 25186627, 28779002, 29522266, 35980532), an individual undergoing clinical genetic testing for Lynch syndrome (PMID: 25980754), and an individual with multiple primary tumors or with a single primary tumor and a first-degree relative with multiple primary tumors (PMID: 29909963). In addition, in case-control studies the variant was present at similar or low frequencies in breast cancer patients compared to control subjects (PMID: 19781682, 28779002). This variant is present 10x 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. -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 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]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 29, 2024	- -

not specified

Benign:2

Benign, no assertion criteria provided	research	King Laboratory, University of Washington	Sep 01, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 31, 2024	Variant summary: ATM c.5821G>C (p.Val1941Leu) results in a conservative amino acid change located in the PIK-related kinase domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251056 control chromosomes, predominantly at a frequency of 0.00026 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing breast/ATM-related cancer and/or Ataxia Telangiectasia. However, the variant was also reported in 10 / 9884 women (i.e. with a frequency of about 0.001), who were older than 70 years of age, and never had cancer (FLOSSIES database), which might suggest a benign outcome for the variant. c.5821G>C has been reported in the literature in individuals affected with breast cancer (e.g. Shayeghi_1998, Renwick_2006, Maxwell_2015, Pereira_2022), other tumor phenotypes such as chronic lymphocytic leukemia (CLL), Lynch syndrome-associated cancer and/or polyps, pediatric low grade glioma (e.g. Skowronska_2011, Yurgelun_2015, Zhang_2015, Tung_2015) and also in several healthy controls (e.g. Tavtigian_2009, Skowronska_2011, Tiao_2017, Yu_2022). Recent case-control studies showed that the frequencies of this variant are similar in cases (breast cancer, prostate cancer, or pancreatic cancer) and controls, indicating this variant does not associate with breast, prostate, or pancreatic cancer (Dorling_2021, Karlsson_2021, Yu_2022). Furthermore, a co-occurrence with another pathogenic variant (BRCA1 c.3607C>T, p.Arg1203X) has been observed for this variant (internal sample). Using an ATM-null lymphoblastoid cell line (LCL) transfected with the variant of interest, Barone et al demonstrated an approximately 50% decrease in protein expression (or stability), yet no significant decrease in specific kinase activity (Barone_2009). The following publications have been ascertained in the context of this evaluation (PMID: 19431188, 33471991, 33436325, 25503501, 35980532, 16832357, 9764584, 21933854, 19781682, 28652578, 25186627, 29909963, 35047863, 25980754, 26580448). ClinVar contains an entry for this variant (Variation ID: 127412). Based on the evidence outlined above, the variant was classified as likely benign. -

Breast and/or ovarian cancer

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Oct 20, 2022

- -

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

Aug 13, 2024

The ATM c.5821G>C variant is predicted to result in the amino acid substitution p.Val1941Leu. This variant has been identified in individuals with breast cancer (Table S2, Renwick et al. 2006. PubMed ID: 16832357; Table S1, Maxwell et al. 2015. PubMed ID: 25503501, Table S4, Bhai et al. 2021. PubMed ID: 34326862), chronic lymphocytic leukemia (Table S2, Skowronska et al. 2012. PubMed ID: 21933854), and suspected Lynch syndrome (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754). Functional analysis showed that this variant results in reduced ATM protein activity (Barone et al. 2009. PubMed ID: 19431188). However, in case-control studies, this variant was identified with similar frequencies between controls and individuals with breast cancer or chronic lymphocytic leukemia (Table S2, Tavtigian et al. 2009. PubMed ID: 19781682; Table S2, Skowronska et al. 2012. PubMed ID: 21933854). This variant is reported in 0.025%of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of pathogenicity in ClinVar ranging from benign to uncertain (http://www.ncbi.nlm.nih.gov/clinvar/variation/127412). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Pathogenic

0.29

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

T;T

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

D;.

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.59

D;D

MetaSVM

Uncertain

-0.12

MutationAssessor

Uncertain

2.6

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.5

N;N

REVEL

Uncertain

0.55

Sift

Benign

0.093

T;T

Sift4G

Benign

0.14

T;T

Polyphen

0.82

P;P

Vest4

0.73

MVP

0.93

MPC

0.34

ClinPred

0.16

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.55

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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