NM_000051.4(ATM):c.8147T>C (p.Val2716Ala) AND Ataxia-telangiectasia syndrome

Germline classification:: Pathogenic/Likely pathogenic (12 submissions)
Last evaluated:: Feb 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:: RCV000169105.38

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)

Name:: Ataxia-telangiectasia syndrome (AT)
Synonyms:: Louis-Bar syndrome; Cerebello-oculocutaneous telangiectasia; Immunodeficiency with ataxia telangiectasia; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008840; MedGen: C0004135; Orphanet: 100; OMIM: 208900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000220304	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (May 13, 2014)	unknown	literature only	PubMed (5) [See all records that cite these PMIDs] 15279808, 16864838, 19535770, 21965147, 11805335 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV000260088	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 2557216, 16864838, 19535770, 21354641, 21965147, 25957637, 26976419, 11805335, 28492532
SCV000328271	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 19605768, 19535770
SCV000918562	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 10, 2018)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21965147, 11805335, 25957637, 16864838 Citation Link,
SCV001149689	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Pathogenic (Jan 10, 2018)	maternal	clinical testing	Citation Link,
SCV001519105	Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 4, 2021)	unknown	research	PubMed (1) [See all records that cite this PMID]
SCV002024401	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 8, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003842120	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 23, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003927266	KCCC/NGS Laboratory, Kuwait Cancer Control Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 31, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004848893	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 2, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005052017	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 1, 2024)	germline	curation	PubMed (1) [See all records that cite this PMID]
SCV005380271	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	not provided	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing, literature only, not provided
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing, research
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	curation
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	maternal	yes	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Functional consequences of sequence alterations in the ATM gene.

Lavin MF, Scott S, Gueven N, Kozlov S, Peng C, Chen P.

DNA Repair (Amst). 2004 Aug-Sep;3(8-9):1197-205. Review.

PubMed [citation]

PMID:: 15279808

Comments on: "Two Routes for Renal 99mTc-DMSA Uptake into the Renal Cortical Tubular Cell".

de Lange MJ, Kosterink JG, Piers DA, van Luijk WH, Meijer S.

Eur J Nucl Med. 1989;15(9):633. No abstract available.

PubMed [citation]

PMID:: 2557216

See all PubMed Citations (12)

Details of each submission

From Counsyl, SCV000220304.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (5)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000260088.12

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

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). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests 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.

#	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		not provided	not provided	not provided	not provided

From GeneReviews, SCV000328271.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000918562.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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.

#	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		not provided	not provided	not provided	not provided

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV001149689.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	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	maternal	yes	1	blood	not provided		1	not provided	not provided	not provided

From Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris, SCV001519105.1

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

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

From Revvity Omics, Revvity, SCV002024401.3

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV003842120.1

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

Description

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.

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

From KCCC/NGS Laboratory, Kuwait Cancer Control Center, SCV003927266.1

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

Description

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.

#	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		1	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848893.1

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

Description

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.

#	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		not provided	not provided	not provided	not provided

From Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV005052017.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, SCV005380271.1

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

#	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

Last Updated: Nov 24, 2024

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