11-108250699-A-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_ModeratePP5_Very_Strong

The NM_000051.4(ATM):c.1236-2A>T variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 26)

Exomes 𝑓: 0.000043 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ATM
NM_000051.4 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 8.80

Publications

16 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):

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

ATM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.040562645 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9.3, offset of 7, new splice context is: ttttttttttttggctacAGatt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PP5

Variant 11-108250699-A-T is Pathogenic according to our data. Variant chr11-108250699-A-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 375249.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	NM_000051.4	MANE Select	c.1236-2A>T		splice_acceptor intron	N/A	NP_000042.3
	ATM	NM_001351834.2		c.1236-2A>T		splice_acceptor intron	N/A	NP_001338763.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ATM	ENST00000675843.1	MANE Select	c.1236-2A>T	splice_acceptor intron	N/A	ENSP00000501606.1
ATM	ENST00000452508.7	TSL:1	c.1236-2A>T	splice_acceptor intron	N/A	ENSP00000388058.2
ATM	ENST00000531525.3	TSL:1	c.1236-2A>T	splice_acceptor intron	N/A	ENSP00000434327.3

Frequencies

GnomAD3 genomes

AF:

0.000175

AC:

AN:

85722

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000404

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:

0.000480

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000281

Gnomad OTH

AF:

0.000873

GnomAD2 exomes

AF:

0.0000770

AC:

AN:

168756

AF XY:

0.0000535

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000134

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000875

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000737

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000431

AC:

AN:

1277532

Hom.:

Cov.:

AF XY:

0.0000425

AC XY:

AN XY:

635658

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000384

AC:

AN:

28654

American (AMR)

AF:

0.000516

AC:

AN:

30984

Ashkenazi Jewish (ASJ)

AF:

0.0000899

AC:

AN:

22236

East Asian (EAS)

AF:

0.00

AC:

AN:

35966

South Asian (SAS)

AF:

0.0000907

AC:

AN:

66128

European-Finnish (FIN)

AF:

0.0000535

AC:

AN:

37370

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3696

European-Non Finnish (NFE)

AF:

0.0000130

AC:

AN:

999792

Other (OTH)

AF:

0.0000949

AC:

AN:

52706

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.280

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000175

AC:

AN:

85770

Hom.:

Cov.:

AF XY:

0.000147

AC XY:

AN XY:

40856

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000403

AC:

AN:

24838

American (AMR)

AF:

0.00

AC:

AN:

8074

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1886

East Asian (EAS)

AF:

0.00

AC:

AN:

3332

South Asian (SAS)

AF:

0.00

AC:

AN:

2606

European-Finnish (FIN)

AF:

0.000480

AC:

AN:

4168

Middle Eastern (MID)

AF:

0.00

AC:

AN:

108

European-Non Finnish (NFE)

AF:

0.000281

AC:

AN:

39200

Other (OTH)

AF:

0.000862

AC:

AN:

1160

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.242

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:

0.0000869

Hom.:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Pathogenic:2

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

Sep 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects an acceptor splice site in intron 9 of the ATM gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individual(s) with breast cancer and ataxia-telangiectasia (PMID: 14695534, 24763289, 30303537). ClinVar contains an entry for this variant (Variation ID: 375249). Studies have shown that disruption of this splice site alters ATM gene expression (PMID: 14695534). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Malignant tumor of urinary bladder

Pathogenic:1

Laboratory of Urology, Hospital Clinic de Barcelona

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Hereditary cancer-predisposing syndrome

Pathogenic:1

Jan 12, 2021

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1236-2A>T intronic pathogenic mutation results from an A to T substitution two nucleotides upstream from coding exon 9 in the ATM gene. This nucleotide position is highly conserved in available vertebrate species. This alteration was identified in 1/1207 cases of French women diagnosed with breast cancer who had a sister with breast cancer and were BRCA1 and BRCA2 negative and 1/1199 general population controls (Girard E et al. Int J Cancer, 2019 04;144:1962-1974). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Another alteration impacting the same acceptor site (c.1236-2A>G) has been identified in multiple individuals with ataxia telangiectasia (A-T) and has been shown to have a similar impact on splicing (Coutinho G et al. Am J Med Genet A, 2004 Apr;126A:33-40). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Familial cancer of breast

Pathogenic:1

Jan 12, 2024

Myriad Genetics, Inc.

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.99

FATHMM_MKL

Pathogenic

0.99

PhyloP100

8.8

GERP RS

5.8

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.94

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.73

Position offset: 9

DS_AL_spliceai

0.94

Position offset: 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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over