NM_000051.4:c.8147T>C

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

9
7
3

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]
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]

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
ATMNM_000051.4 linkc.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
ATMENST00000675843.1 linkc.8147T>C p.Val2716Ala missense_variant Exon 55 of 63 NM_000051.4 ENSP00000501606.1 Q13315

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152218
Hom.:
0
Cov.:
32
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:
8
AN:
251342
Hom.:
0
AF XY:
0.0000294
AC XY:
4
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:
37
AN:
1461762
Hom.:
0
Cov.:
31
AF XY:
0.0000234
AC XY:
17
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:
7
AN:
152218
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
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.:
0
Bravo
AF:
0.0000302
ExAC
AF:
0.0000412
AC:
5
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

- -

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, Medical Genetics
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. -

-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

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 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

- -

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

- -

Sep 08, 2019
Revvity Omics, Revvity
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

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. -

not provided Pathogenic:10
-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jun 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ATM: PM3:Strong, PP1:Strong, PM2, PP3, PS3:Supporting, PS4:Supporting -

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. -

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) -

Mar 08, 2024
Mayo Clinic Laboratories, Mayo Clinic
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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 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. -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Familial cancer of breast Pathogenic:8
Sep 10, 2024
Department of Human Genetics, Hannover Medical School
Significance: 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

- -

Mar 28, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 08, 2022
MGZ Medical Genetics Center
Significance: Likely 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
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; M&eacute;neret 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. -

Sep 10, 2021
Sema4, Sema4
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: curation

- -

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. -

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. -

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

PS3_Moderate, PS4_Moderate (for AD cancers) or PM3_Strong (for AR ataxia-telangiectasia), PM2_Moderate, PP3_Supporting -

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

- -

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 -

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. -

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
D
BayesDel_noAF
Pathogenic
0.40
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.34
T;T
Eigen
Pathogenic
0.72
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.88
D;.
M_CAP
Uncertain
0.29
D
MetaRNN
Pathogenic
0.96
D;D
MetaSVM
Uncertain
0.72
D
MutationAssessor
Uncertain
2.1
M;M
PrimateAI
Uncertain
0.76
T
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
D
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.

Other links and lift over

dbSNP: rs587782652; hg19: chr11-108205832; API