rs786203059

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000615746.4(C11orf65):c.*1278A>G variant causes a 3 prime UTR change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000996 in 1,606,236 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

C11orf65
ENST00000615746.4 3_prime_UTR

Scores

Splicing: ADA: 0.9921

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:5

Conservation

PhyloP100: 7.77

Publications

3 publications found

Variant links:

COSMIC-nc: COSV105845378

Genes affected

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:

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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4 link	c.7629+2T>C		splice_donor_variant, intron_variant	Intron 51 of 62	ENST00000675843.1	NP_000042.3	Q13315A0A024R3C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 link	c.7629+2T>C		splice_donor_variant, intron_variant	Intron 51 of 62		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151898

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000403

AC:

AN:

248366

AF XY:

0.00000744

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:

0.00

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1454338

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

723074

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33316

American (AMR)

AF:

0.00

AC:

AN:

44118

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25934

East Asian (EAS)

AF:

0.00

AC:

AN:

39384

South Asian (SAS)

AF:

0.00

AC:

AN:

83970

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52930

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5584

European-Non Finnish (NFE)

AF:

0.0000135

AC:

AN:

1109054

Other (OTH)

AF:

0.00

AC:

AN:

60048

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

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:

0.00000658

AC:

AN:

151898

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74200

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41380

American (AMR)

AF:

0.00

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10498

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67964

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

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:

0.0000150

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Pathogenic:1Uncertain:1

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects a donor splice site in intron 51 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). This variant is present in population databases (rs786203059, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with a personal or family history of cancer (PMID: 31843900, 34262154). ClinVar contains an entry for this variant (Variation ID: 186579). Studies have shown that disruption of this splice site is associated with altered splicing; however, the splicing effect is incomplete and of unknown impact on protein function (PMID: 31843900, external communication; internal data). 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. -

Sep 16, 2020

Natera, Inc.

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Familial cancer of breast

Pathogenic:1Uncertain:1

Dec 24, 2023

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 01, 2019

King Laboratory, University of Washington

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Sep 17, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.7629+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 50 in the ATM gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. However, +2T>C alterations are capable of generating wild-type transcripts in some genomic contexts and should be interpreted with caution (Lin JH et al. Hum Mutat. 2019 10;40:1856-1873). A published RNA study performed on a heterozygous carrier of this variant identified only 24% of the total transcripts as abnormal (Casadei S et al. Proc Natl Acad Sci U S A, 2019 Dec). This suggests that there may be some normal splicing associated with this variant. Internal RNA studies have also suggested that this alteration results in an incomplete splice defect; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Jul 09, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant causes a T to C nucleotide substitution at the +2 position of intron 51 of the ATM gene, replacing a GT donor site with a GC donor site which may be functional (PMID: 31131953). An RNA study from patient-derived lymphoblasts carrying this variant showed 76% of transcripts were full length, 19% of transcripts had exon 51 skipping (partial in-frame deletion of the FAT domain) and 5% of transcripts used a cryptic donor site that caused a 4 base insertion and premature stop signal (PMID: 31843900). This suggests that the variant is hypomorphic and up to 50% of variant pre-mRNA could be spliced into full-length transcript. Additional RNA studies have reported similar results with an incomplete splice defect of unknown clinical consequence (ClinVar Accession: SCV000216973.9, SCV000826093.7). This variant has been reported in individuals affected with breast cancer (Color Health internal data; external communications), an individual affected with prostate cancer (PMID: 32694154), and an individual affected with melanoma (PMID: 34262154). In one suspected hereditary breast cancer family, three affected siblings carried this variant (PMID: 31843900, external communications). This variant has been identified in 1/248366 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease and the influence of genetic background conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Dec 18, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Canonical splice site variant demonstrated to result in a partial splicing defect leading to multiple transcripts, a majority of which are full-length (PMID: 31843900); In silico analysis supports a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); Identified in individuals with prostate cancer, melanoma, or osteosarcoma in published literature (PMID: 32694154, 34262154, 32191290); This variant is associated with the following publications: (PMID: 34262154, 23532176, 32694154, 31843900, 32191290) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Pathogenic

1.0

PhyloP100

7.8

ClinPred

0.94

GERP RS

5.6

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Benign

0.64

Splicevardb

3.0

SpliceAI score (max)

0.49

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.41

Position offset: 2

DS_DL_spliceai

0.49

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over