dbSNP rs587782652: ATM:p.Val2716Ala (chr11-108335105-T-C) – ACMG Classification: Pathogenic (20 pts)

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3PM1PM5PP3_StrongPP5_Very_Strong

The NM_000051.4(ATM):c.8147T>C(p.Val2716Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000187129: This alteration has been associated with reduced ATM protein expression, decreased ATM kinase activity, and increased radiosensitivity in studies using A-T lymphoblastoid cell lines (Demuth I et al. Neurogenetics. 2011 Nov" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2716I) has been classified as Uncertain significance. The gene ATM is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:47O:1

Conservation

PhyloP100: 7.63

Publications

60 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 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

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: Pathogenic. The variant received 20 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000187129: This alteration has been associated with reduced ATM protein expression, decreased ATM kinase activity, and increased radiosensitivity in studies using A-T lymphoblastoid cell lines (Demuth I et al. Neurogenetics. 2011 Nov;12:273-82; Scott SP et al. Proc. Natl. Acad. Sci. U.S.A. 2002 Jan;99:925-30).; SCV000682458: A functional study has shown that the variant results in the loss of ATM kinase activity and increased radiosensitivity (PMID: 11805335).; SCV006311234: experimental studies have shown that this missense change reduces ATM kinase activity and increases radiosensitivity (PMID:11805335).; SCV006324743: Functional studies have shown that this variant decreases ATM kinase activity, lowers ATM protein levels and increases radiosensitivity in a transfection model (PMID: 11805335) (PS3_Moderate).; SCV000260088: Experimental studies have shown that this missense change affects ATM function (PMID: 11805335).; SCV000918562: The most pronounced variant effect results in <10% of normal activity (Scott_2001).; SCV003927266: Experimental studies have shown that this missense change affects ATM function (PMID: 11805335).; SCV004848893: "In vitro functional studies provide some evidence that this variant reduces, however retains some protein function, which may produce the more mild symptoms seen in patients." PMID:11805335, PMID:21965147; SCV000209770: Published functional studies support a damaging effect: expresses some level of kinase activity, but shows reduced ATM protein expression and transfected cells have exhibited reduced radiation-induced kinase activity (Scott 2002, Verhagen 2009, Demuth 2011, Reiman 2011); SCV001475572: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 11805335); SCV002064359: Functional in-vitro studies demonstrated that p.Val2716Ala-infected cells had higher radiation-induced chromosome aberrations, when compared to controls (PMID: 11805335).; SCV000839884: "This variant is located in the kinase domain and in vitro data showed reduced kinase activity and lower ATM protein [PMID 11805335]."; SCV004724027: This variant has been shown to have a reduction or abolished kinase activity (Scott et al. 2002. PubMed ID: 11805335; Demuth et al. 2011. PubMed ID: 21965147).

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 50 uncertain in NM_000051.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-108335104-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 181985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.959

PP5

Variant 11-108335105-T-C is Pathogenic according to our data. Variant chr11-108335105-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 142700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

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

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATM	NM_000051.4	MANE Select	c.8147T>C	p.Val2716Ala	missense	Exon 55 of 63	NP_000042.3
ATM	NM_001351834.2		c.8147T>C	p.Val2716Ala	missense	Exon 56 of 64	NP_001338763.1	Q13315
C11orf65	NM_001330368.2		c.641-26034A>G		intron	N/A	NP_001317297.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATM	ENST00000675843.1	MANE Select	c.8147T>C	p.Val2716Ala	missense	Exon 55 of 63	ENSP00000501606.1	Q13315
ATM	ENST00000452508.7	TSL:1	c.8147T>C	p.Val2716Ala	missense	Exon 56 of 64	ENSP00000388058.2	Q13315
C11orf65	ENST00000615746.4	TSL:1	c.*1269+115A>G		intron	N/A	ENSP00000483537.1	Q8NCR3-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000318

AC:

AN:

251342

AF XY:

0.0000294

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1461762

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727176

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000324

AC:

AN:

1111946

Other (OTH)

AF:

0.0000166

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2092

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

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

Alfa

AF:

0.0000789

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Ataxia-telangiectasia syndrome (13)

not provided (12)

Familial cancer of breast (10)

Hereditary cancer-predisposing syndrome (6)

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast (2)

ATM-related disorder (1)

Breast and/or ovarian cancer (1)

Breast carcinoma (1)

Tip-toe gait (1)

Uterine corpus cancer (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.40

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

M_CAP

Uncertain

0.29

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.72

MutationAssessor

Uncertain

2.1

PhyloP100

7.6

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.4

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

Sift4G

Benign

0.079

Polyphen

0.99

Vest4

0.94

MutPred

0.87

Loss of stability (P = 0.0711)

MPC

0.64

ClinPred

0.87

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.71

gMVP

0.70

Mutation Taster

=7/93

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over