NM_000051.4(ATM):c.8147T>C (p.Val2716Ala) AND not provided

Germline classification:: Pathogenic (10 submissions)
Last evaluated:: Jun 1, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000212079.44

Allele description [Variation Report for NM_000051.4(ATM):c.8147T>C (p.Val2716Ala)]

NM_000051.4(ATM):c.8147T>C (p.Val2716Ala)

Genes:

ATM:ATM serine/threonine kinase [Gene - OMIM - HGNC]
C11orf65:chromosome 11 open reading frame 65 [Gene - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q22.3

Genomic location:

Preferred name:

NM_000051.4(ATM):c.8147T>C (p.Val2716Ala)

Other names:

p.V2716A:GTT>GCT

HGVS:

NC_000011.10:g.108335105T>C
NG_009830.1:g.117274T>C
NG_054724.1:g.139728A>G
NM_000051.4:c.8147T>CMANE SELECT
NM_001330368.2:c.641-26034A>G
NM_001351110.2:c.*38+115A>G
NM_001351834.2:c.8147T>C
NP_000042.3:p.Val2716Ala
NP_000042.3:p.Val2716Ala
NP_000042.3:p.Val2716Ala
NP_001338763.1:p.Val2716Ala
LRG_135t1:c.8147T>C
LRG_135:g.117274T>C
LRG_135p1:p.Val2716Ala
NC_000011.9:g.108205832T>C
NM_000051.3:c.8147T>C
p.V2716A

Protein change:

V2716A

Links:

dbSNP: rs587782652

NCBI 1000 Genomes Browser:

rs587782652

Molecular consequence:

NM_001330368.2:c.641-26034A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.*38+115A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000051.4:c.8147T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.8147T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000209770	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jul 29, 2022)	germline	clinical testing	Citation Link,
SCV001475572	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Dec 20, 2022)	unknown	clinical testing	PubMed (20) [See all records that cite these PMIDs] 25122203, 25572163, 25957637, 25980754, 26681312, 26976419, 30322717, 28843361, 30579816, 30549301, 30819809, 29909963, 28126470, 21778326, 11805335, 16864838, 19535770, 21965147, 22213089, 26467025
SCV001713587	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 7, 2020)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 31050087, 30579816, 30549301, 30819809, 25572163, 19535770, 25741868
SCV001740397	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001906005	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001955835	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002010779	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 3, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002036099	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002064359	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 17, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002497176	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Jun 1, 2024)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	6	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The pleiotropic movement disorders phenotype of adult ataxia-telangiectasia.

Méneret A, Ahmar-Beaugendre Y, Rieunier G, Mahlaoui N, Gaymard B, Apartis E, Tranchant C, Rivaud-Péchoux S, Degos B, Benyahia B, Suarez F, Maisonobe T, Koenig M, Durr A, Stern MH, Dubois d'Enghien C, Fischer A, Vidailhet M, Stoppa-Lyonnet D, Grabli D, Anheim M.

Neurology. 2014 Sep 16;83(12):1087-95. doi: 10.1212/WNL.0000000000000794. Epub 2014 Aug 13.

PubMed [citation]

PMID:: 25122203

Clinical variability in ataxia-telangiectasia.

Lohmann E, Krüger S, Hauser AK, Hanagasi H, Guven G, Erginel-Unaltuna N, Biskup S, Gasser T.

J Neurol. 2015 Jul;262(7):1724-7. doi: 10.1007/s00415-015-7762-z. Epub 2015 May 10.

PubMed [citation]

PMID:: 25957637

See all PubMed Citations (22)

Details of each submission

From GeneDx, SCV000209770.16

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Athena Diagnostics, SCV001475572.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (20)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV001713587.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (7)

Description

PS3, PS4, PM2, PM3, PP3, PP4, PP5

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		1	not provided	not provided	not provided

From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001740397.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute - VKGL Data-share Consensus, SCV001906005.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001955835.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden, SCV002010779.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus, SCV002036099.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetic Services Laboratory, University of Chicago, SCV002064359.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV002497176.16

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	6	not provided	not provided	clinical testing	not provided

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		6	not provided	not provided	not provided

Last Updated: Nov 24, 2024

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