chr11-108249096-T-C

Variant names:

Variant summary

Our verdict is The variant received -9 classification points (ACMG Germline Pathogenicity v2019). BS2BP4BP6_Strong

The NM_000051.4(ATM):c.1229T>C (p.Val410Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00282 (AC=4,554) in the gnomAD database across 1,613,936 control chromosomes, including 11 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.00337. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.V410L: Uncertain_significance (ClinVar VariationId 3967210, 1 star); p.V410M: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 216190); p.V410= (synonymous): Likely_benign (ClinVar VariationId 453357, 2 stars); p.V410= (synonymous): Likely_benign (ClinVar VariationId 1155205, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

Frequency

Genomes: 𝑓 0.0018 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0029 ( 9 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:28O:1

Conservation

PhyloP100: 7.12

Publications

74 publications found

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 Gene-Disease associations (from GenCC):

ATM-related cancer predisposition
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
hereditary breast carcinoma
Inheritance: AD Classification: DEFINITIVE Submitted by: Natera, Ambry Genetics
ataxia telangiectasia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, ClinGen, G2P, Orphanet, Natera, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
prostate cancer
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
sarcoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
gastric carcinoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
hereditary nonpolyposis colon cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ATM links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000051.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Specifications for ATM are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -9 points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Supporting).

BP6

ClinVar 0-star benign — supporting (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 0 star(s). ClinVar submissions strongly and reliably favor benignity (22/24 total B/LB).

BS2

≥2 homozygotes in gnomAD — observed in healthy adults (BS2); GnomAD homozygous count = 11.; Very high cumulative gnomAD AC = 4554 (any gene).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000051.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	NM_000051.4	MANE Select	c.1229T>C	p.Val410Ala	missense	Exon 9 of 63	NP_000042.3
	ATM	NM_001351834.2		c.1229T>C	p.Val410Ala	missense	Exon 10 of 64	NP_001338763.1	Q13315

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATM	ENST00000675843.1	MANE Select	c.1229T>C	p.Val410Ala	missense	Exon 9 of 63	ENSP00000501606.1	Q13315
ATM	ENST00000452508.7	TSL:1	c.1229T>C	p.Val410Ala	missense	Exon 10 of 64	ENSP00000388058.2	Q13315
ATM	ENST00000531525.3	TSL:1	c.1229T>C	p.Val410Ala	missense	Exon 9 of 30	ENSP00000434327.3	H0YDU7

Frequencies

GnomAD3 genomes

AF:

0.00185

AC:

281

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00393

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00275

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00222

AC:

558

AN:

251102

AF XY:

0.00229

show subpopulations

Gnomad AFR exome

AF:

0.000924

Gnomad AMR exome

AF:

0.00298

Gnomad ASJ exome

AF:

0.00417

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000925

Gnomad NFE exome

AF:

0.00339

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.00292

AC:

4273

AN:

1461656

Hom.:

Cov.:

AF XY:

0.00278

AC XY:

2021

AN XY:

727132

show subpopulations

African (AFR)

AF:

0.000836

AC:

AN:

33476

American (AMR)

AF:

0.00304

AC:

136

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00291

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.000225

AC:

AN:

53368

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00346

AC:

3844

AN:

1111918

Other (OTH)

AF:

0.00290

AC:

175

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

208

416

624

832

1040

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

140

280

420

560

700

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00185

AC:

281

AN:

152280

Hom.:

Cov.:

AF XY:

0.00192

AC XY:

143

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.000601

AC:

AN:

41570

American (AMR)

AF:

0.00392

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00275

AC:

187

AN:

68008

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

TOPMed (Bravo)

AF:

0.00230

ALFA (dbGaP/dbSNP Allele Frequency Aggregator)

AF:

0.00303

AC:

1109

AN:

366086

Hom.:

Local populations

ABraOM SABE-WGS-1171

AF:

0.00683

AC:

AN:

2342

Hom.:

ESP6500 (Exome Variant Server)

AF:

0.00177

AC:

AN:

12998

show subpopulations

European American

AF:

0.00221

AC:

AN:

8596

African American

AF:

0.000909

AC:

AN:

4402

Turkish Variome

AF:

0.000885

AC:

AN:

5176

Hom.:

UK10K

AF:

0.00331

AC:

AN:

7562

show subpopulations

TwinsUK

AF:

0.00308

AC:

AN:

3574

ALSPAC

AF:

0.00363

AC:

AN:

3854

Case/control cohorts

Cohort

Cases

Controls

ASC

(Autism)

21 / 11112AF: 0.00188985

48 / 17618AF: 0.00272449

BipEx

(Bipolar disorder (including schizoaffective))

103 / 28420AF: 0.00362421

77 / 28844AF: 0.00266953

Epi25

(Epilepsy)

107 / 41958AF: 0.00255017

226 / 66888AF: 0.00337878

SCHEMA

(Schizophrenia)

291 / 122052AF: 0.00238423

589 / 191192AF: 0.00308067

Allele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (8)

Ataxia-telangiectasia syndrome (6)

Hereditary cancer-predisposing syndrome (6)

not specified (6)

ATM-related disorder (1)

Breast and/or ovarian cancer (1)

Carcinoma of colon (1)

Familial cancer of breast (1)

Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.088

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.77

M_CAP

Benign

0.031

MetaRNN

Benign

0.012

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

PhyloP100

7.1

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.26

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0070

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

VESM-3B

Benign

-6.3

(source)

FuncVEP CTI

Benign

0.029

(source)

AlphaGenome AVI

Pathogenic

(source)

GPN-Star LLR

-5.8

(source)

GPN-Star score

5.8

(source)

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Pangolin (max)

Benign

0.0

(source)

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

Case/control cohorts

ClinVar

Computational scores

Splicing

Publications

Other links and lift over