NM_000051.4:c.8147T>C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_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 (★★).

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:40O:1

Conservation

PhyloP100: 7.63

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 Pathogenic. Variant got 12 ACMG points.

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 [Likely_pathogenic]. Clinvar id is 142700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108335105-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4 link	c.8147T>C	p.Val2716Ala	missense_variant	Exon 55 of 63	ENST00000675843.1	NP_000042.3	Q13315A0A024R3C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 link	c.8147T>C	p.Val2716Ala	missense_variant	Exon 55 of 63		NM_000051.4	ENSP00000501606.1		Q13315

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

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251342

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135850

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000324

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000980

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:40Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome

Pathogenic:11Other:1

May 13, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 10, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATM c.8147T>C (p.Val2716Ala) results in a non-conservative amino acid change located in the Phosphatidylinositol 3-/4-kinase, catalytic domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 277104 control chromosomes (gnomAD). The variant, c.8147T>C, has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (Demuth_2011, Hiel_2006, Lohmann_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Scott_2001). Five ClinVar submission from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jan 10, 2018

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 02, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Val2716Ala variant in ATM has been reported in >20 compound heterozygous individuals with ataxia telangectasia and segregated with disease in 3 affected individuals from 2 families. Most of these cases, however are atypical and mild cases of ataxia telangectasia (Verhagen 2009 PMID: 19535770, van Os 2019 PMID: 30819809, Schon 2019 PMID: 30549301, Lohmann 2015 PMID: 25957637, Fievet 2019 PMID: 31050087, Heil 2006 PMID: 16864838, Demuth 2011 PMID: 21965147, Reiman 2011 PMID: 21792198). It has also been found in individuals with breast cancer (Reiman 2011 PMID: 21792198, Mandigers 2011 PMID: 21354641, Fanale 2020 PMID: 32854451, Susswein 2016 PMID: 26681312). It has also been identified in 0.0088% (6/68034) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 142700). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. 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 (Scott 2002 PMID: 11805335, Demuth 2011 PMID: 21965147). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive ataxia telangectasia, though presentation may be atypical. ACMG/AMP Criteria applied: PM3_Very Strong, PP1_Strong, PS3_Moderate, PM2_Supporting, PP3. -

Sep 08, 2019

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 31, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ATM family pathogenic mutation was detected in this specimen as heterozygous .The mutation detected in the son segregated with this finding .This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 2716 of the ATM protein (p.Val2716Ala). This variant is present in population databases (rs587782652, gnomAD 0.005%).This amino acid position is highly conserved. This missense change has been observed in individual(s) with ataxia-telangiectasia (A-T), generalized dystonia, breast cancer, and dystonia (PMID: 2557216, 16864838, 19535770, 21354641, 21965147, 25957637, 26976419) and others . ClinVar contains an entry for this variant (Variation ID: 142700) classified as Pathogenic/Likely pathogenic by multiples submitters . In silico analysis supports that this missense variant has a deleterious effect on protein structure/function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ATM function (PMID: 11805335). For these reasons, this variant has been classified as Pathogenic. Homozygous or compound pathogenic/likely pathogenic mutations in the ATM gene are known to cause Ataxia- Telangiectasia. Heterozygous pathogenic/likely pathogenic mutations in the ATM gene are associated with increased risk of certain cancers. -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 2716 of the ATM protein (p.Val2716Ala). This variant is present in population databases (rs587782652, gnomAD 0.005%). This missense change has been observed in individual(s) with ataxia-telangiectasia (A-T), generalized dystonia, breast cancer, and dystonia (PMID: 2557216, 16864838, 19535770, 21354641, 21965147, 25957637, 26976419). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 142700). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ATM protein function. Experimental studies have shown that this missense change affects ATM function (PMID: 11805335). For these reasons, this variant has been classified as Pathogenic. -

Jan 04, 2021

Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Feb 23, 2023

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.74). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000142700) and a different missense change at the same codon (p.Val2716Phe / ClinVar ID: VCV000181985) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:10

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 08, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 29, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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); Observed in the heterozygous state in individuals with ATM-related cancers (Mandigers 2011, Reiman 2011, Huang 2018, Whitworth 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26053094, 25572163, 25525159, 21792198, 22146522, 26976419, 30579816, 30549301, 21965147, 21778326, 25957637, 19535770, 25040471, 25980754, 11805335, 16864838, 21354641, 25793145, 26681312, 27060149, 10738255, 15279808, 23566627, 28477129, 28301460, 28126470, 28716242, 25122203, 28843361, 22213089, 29478780, 29909963, 30322717, 30819809, 20301790, 19605768, 31050087, 31920950, 32854451, 32558426, 31980526, 29625052, 33098801, 31447099, 31589614, 23532176, 33594163) -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATM: PM3:Very Strong, PP1:Strong, PS3:Moderate, PM2:Supporting, PP3 -

Dec 20, 2022

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant segregates with ataxia-telangiectasia in at least one family. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 11805335) In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. -

Mar 17, 2020

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the ATM gene demonstrated a sequence change, c.8147T>C, in exon 55 that results in an amino acid change, p.Val2716Ala. This sequence change has been described in the EXAC database with a low population frequency of 0.004% (dbSNP rs587782652).The p.Val2716Ala change affects a highly conserved amino acid residue located in a domain of the ATM protein that is known to be functional. The p.Val2716Ala substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been described in patients with ataxia-telangiectasia in compound heterozygous state (PMID: 21965147, 19535770). Functional in-vitro studies demonstrated that p.Val2716Ala-infected cells had higher radiation-induced chromosome aberrations, when compared to controls (PMID: 11805335). These collective evidences suggest that this sequence change is pathogenic. -

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Familial cancer of breast

Pathogenic:8

Feb 08, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 02, 2020

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 10, 2024

Department of Human Genetics, Hannover Medical School

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 14, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

_x000D_ Criteria applied: PS3, PS4_MOD -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 05, 2017

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This c.8147T>C (p.Val2716Ala) has previously been reported in compound heterozygous patients with ataxia telangiectasia most of them diagnosed in adulthood [PMID 19535770, 16864838, 21965147]. This variant is located in the kinase domain and in vitro data showed reduced kinase activity and lower ATM protein [PMID 11805335]. This variant was observed in 5 individuals at the heterozygous state in the ExAC database (http://exac.broadinstitute.org/variant/11-108205832-T-C). Valine at amino acid position 2716 of the ATM protein is conserved in mammals. While not validated for clinical use, computer-based algorithms SIFT and Polyphen-2 did not yield concordant predictions regarding the pathogenicity of the change. It is thus interpreted as a likely pathogenic variant. However, the estimated cancer risk for this variant has not been determined. -

Dec 09, 2022

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PS3_MOD, PM3_VSTR , PM5 -

Hereditary cancer-predisposing syndrome

Pathogenic:4

Jan 26, 2018

Academic Department of Medical Genetics, University of Cambridge

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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. -

Sep 23, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V2716A variant (also known as c.8147T>C), located in coding exon 54 of the ATM gene, results from a T to C substitution at nucleotide position 8147. The valine at codon 2716 is replaced by alanine, an amino acid with similar properties. This alteration has been reported together with second known pathogenic ATM mutations in multiple individuals with milder, "variant ataxia-telangiectasia" (Verhagen MM et al. Neurology. 2009 Aug;73:430-7; Demuth I et al. Neurogenetics. 2011 Nov;12:273-82; Méneret A, Neurology. 2014 Sep;83:1087-95; Lohmann E et al. J. Neurol. 2015 Jul;262:1724-7; van Os NJH et al. J. Med. Genet., 2019 May;56:308-316; Galatolo D et al. Int J Mol Sci, 2021 Aug;22:). Additionally, this alteration was reported in three unrelated women with ataxia-telangiectasia and breast cancer (Mandigers C et al. Radiother Oncol. 2011 Apr;99:97-8; Reiman A et al. Br. J. Cancer. 2011 Aug;105:586-91). In a multi-gene panel study of patients with bilateral breast cancer, this variant was observed in 1/139 cases (Fanale D et al. Cancers (Basel) 2020 Aug;12(9)). This alteration was also identified in an individual diagnosed with prostate cancer (Wokoorczyk D et al. Int J Cancer, 2020 Nov;147:2793-2800). 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). Another alteration at the same codon, p.V2716F (c.8146G>T), has been detected in an individual with a clinical diagnosis of ataxia telangiectasia (Hersby DS et al. J Pediatr Hematol Oncol. 2015 Mar;37(2):154-5). 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 majority of available evidence to date, this variant is likely to be pathogenic. -

Oct 03, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces valine with alanine at codon 2716 of the kinase domain of ATM protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that the variant results in the loss of ATM kinase activity and increased radiosensitivity (PMID: 11805335). This variant has been reported in many individuals affected with breast cancer (PMID: 26681312, 26976419, 32854451, 33471991). In a large international case-control study, this variant was reported in 16/60466 breast cancer cases and 6/53461 controls (OR=2.358, 95%CI 0.923 to 6.027, p-value=0.086; PMID: 33471991). This variant has been reported in individuals affected with classic ataxia telangiectasia (PMID: 31050087) and atypical, late-onset ataxia telangiectasia (PMID: 25957637, 16864838, 21354641, 19535770, 21965147, 30819809). This variant has been identified in 9/282750 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Sep 10, 2021

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast

Pathogenic:2

Sep 26, 2022

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jan 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast and/or ovarian cancer

Pathogenic:1

Oct 28, 2022

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ATM-related disorder

Pathogenic:1

Jul 31, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ATM c.8147T>C variant is predicted to result in the amino acid substitution p.Val2716Ala. This variant has been reported in individuals with ataxia telangiectasia and 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). More recently, this variant has been identified in individuals with breast cancer (Table S1, Susswein et al. 2016. PubMed ID: 26681312), colorectal cancer (Table S10, Al Dubayan et al. 2018. PubMed ID: 29478780) and in the tumor of an individual with unspecified cancer type (Whitworth et al. 2018. PubMed ID: 29909963). This variant is reported in 0.0054% of alleles in individuals of European (non-Finnish) descent in gnomAD and is classified in ClinVar as pathogenic or likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/142700/). This variant is interpreted as pathogenic. -

Tip-toe gait

Pathogenic:1

Jan 10, 2023

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Gait disorder -

Uterine corpus cancer

Pathogenic:1

Feb 21, 2023

CZECANCA consortium

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breast carcinoma

Pathogenic:1

Sep 12, 2021

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.40

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

T;T

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

D;.

M_CAP

Uncertain

0.29

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Uncertain

0.72

MutationAssessor

Uncertain

2.1

M;M

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.4

D;D

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

0.079

T;T

Polyphen

0.99

D;D

Vest4

0.94

MutPred

0.87

Loss of stability (P = 0.0711);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

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

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