VCV000142700.80 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(41)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 142700 Accession: VCV000142700.80

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q22.3 11: 108335105 (GRCh38) [ NCBI UCSC ] 11: 108205832 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 29, 2015	Oct 26, 2024	Sep 10, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000051.4:c.8147T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000042.3:p.Val2716Ala	missense
NM_001330368.2:c.641-26034A>G		intron variant
NM_001351110.2:c.*38+115A>G		intron variant
NM_001351834.2:c.8147T>C	NP_001338763.1:p.Val2716Ala	missense
NC_000011.10:g.108335105T>C
NC_000011.9:g.108205832T>C
NG_009830.1:g.117274T>C
NG_054724.1:g.139728A>G
LRG_135:g.117274T>C
LRG_135t1:c.8147T>C	LRG_135p1:p.Val2716Ala

... more HGVS ... less HGVS

Protein change

V2716A

Other names

p.V2716A:GTT>GCT

Canonical SPDI

NC_000011.10:108335104:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00003

Trans-Omics for Precision Medicine (TOPMed) 0.00003

Exome Aggregation Consortium (ExAC) 0.00004

The Genome Aggregation Database (gnomAD) 0.00004

Links

ClinGen: CA294465 dbSNP: rs587782652 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ATM		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	10850	17460
C11orf65	-	-	-	GRCh38 GRCh37	3	6592

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Hereditary cancer-predisposing syndrome	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Oct 3, 2023	RCV000132066.30
Ataxia-telangiectasia syndrome	Pathogenic/Likely pathogenic (12)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000169105.38
not provided	Pathogenic (10)	criteria provided, multiple submitters, no conflicts	Jun 1, 2024	RCV000212079.44
Familial cancer of breast	Pathogenic/Likely pathogenic (8)	criteria provided, multiple submitters, no conflicts	Sep 10, 2024	RCV000709709.21
Breast carcinoma	Pathogenic (1)	no assertion criteria provided	Sep 12, 2021	RCV001640164.9
Ataxia-telangiectasia syndrome Familial cancer of breast	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Sep 26, 2022	RCV002285144.9
Uterine corpus cancer	Pathogenic (1)	no assertion criteria provided	Feb 21, 2023	RCV003128150.8
Tip-toe gait	Likely pathogenic (1)	no assertion criteria provided	Jan 10, 2023	RCV003318553.9
Breast and/or ovarian cancer	Likely pathogenic (1)	criteria provided, single submitter	Oct 28, 2022	RCV003492629.1
ATM-related disorder	Pathogenic (1)	no assertion criteria provided	Jul 31, 2024	RCV004551268.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Jun 05, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: germline	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine Accession: SCV000839884.1 First in ClinVar: Oct 14, 2018 Last updated: Oct 14, 2018	Comment: 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 … (more) 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. (less)
Likely pathogenic (Jan 26, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Hereditary cancer-predisposing syndrome Affected status: yes Allele origin: germline	Academic Department of Medical Genetics, University of Cambridge Accession: SCV000992207.1 First in ClinVar: Sep 08, 2019 Last updated: Sep 08, 2019 Comment: Identified as part of research study of individuals with multiple primary tumours referred for genetic assessment	Comment: 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. Clinical Features: Breast carcinoma (present) , Adenocarcinoma of the large intestine (present)
Pathogenic (Jan 10, 2018)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Ataxia-telangiectasia syndrome (Autosomal recessive inheritance) Affected status: yes Allele origin: maternal	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV001149689.1 First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020	Sex: male Tissue: blood
Likely pathogenic (Feb 08, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002579808.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PS4_MOD, PM3, PS3_SUP, PM2_SUP, PP3	Number of individuals with the variant: 2 Sex: male
Likely pathogenic (May 13, 2014)	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015)) Method: literature only	Ataxia-telangiectasia syndrome (Autosomal recessive inheritance) Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000220304.2 First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022	Publications: PubMed (5) PubMed: 15279808‚ 16864838‚ 19535770‚ 21965147‚ 11805335
Pathogenic (Jul 29, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000209770.16 First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (Dec 20, 2022)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV001475572.2 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2024	Publications: PubMed (19) PubMed: 25122203‚ 25572163‚ 25957637‚ 25980754‚ 26681312‚ 26976419‚ 30322717‚ 28843361‚ 30579816‚ 30549301‚ 30819809‚ 29909963‚ 28126470‚ 21778326‚ 11805335‚ 16864838‚ 19535770‚ 21965147‚ 22213089 Comment: 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 … (more) 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. (less)
Pathogenic (Oct 03, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000682458.5 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024	Publications: PubMed (12) PubMed: 11805335‚ 16864838‚ 19535770‚ 21354641‚ 21965147‚ 25957637‚ 26681312‚ 26976419‚ 30819809‚ 31050087‚ 32854451‚ 33471991 Comment: 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 … (more) 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. (less)
Pathogenic (Mar 28, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004209410.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Sep 10, 2018)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Ataxia-telangiectasia syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000918562.1 First in ClinVar: Jun 03, 2019 Last updated: Jun 03, 2019	Publications: PubMed (4) PubMed: 21965147‚ 11805335‚ 25957637‚ 16864838 Comment: 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 … (more) 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. (less)
Likely pathogenic (Apr 02, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: yes Allele origin: germline	Department of Molecular Diagnostics, Institute of Oncology Ljubljana Accession: SCV001499609.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021
Pathogenic (Jan 04, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Ataxia-telangiectasia syndrome Affected status: yes Allele origin: unknown	Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris Accession: SCV001519105.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021
Pathogenic (Mar 17, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002064359.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022	Comment: 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 … (more) 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. (less)
Pathogenic (Apr 14, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001429219.2 First in ClinVar: Aug 17, 2020 Last updated: Apr 30, 2022	Comment: _x000D_ Criteria applied: PS3, PS4_MOD
Pathogenic (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002518542.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
Pathogenic (Sep 10, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002527130.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The ATM c.8147T>C (p.V2716A) variant has been reported in heterozygosity in multiple individuals with breast, lung, and colorectal cancer (PMID: 26681312, 32854451, 28843361, 29478780) and … (more) The ATM c.8147T>C (p.V2716A) variant has been reported in heterozygosity in multiple individuals with breast, lung, and colorectal cancer (PMID: 26681312, 32854451, 28843361, 29478780) and as compound heterozygous in at least 4 individuals with ataxia-telangiectasia (PMID: 30549301). Functional studies have shown that this variant decreases ATM kinase activity (PMID: 11805335, 21792198). This variant was observed in 9/282750 chromosomes in the European (non-Finnish) population, according to the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID: 142700). Based on the current evidence available, this variant is interpreted as pathogenic. (less)	Publications: PubMed (7) PubMed: 26681312‚ 32854451‚ 28843361‚ 29478780‚ 30549301‚ 11805335‚ 21792198
Likely pathogenic (Sep 26, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Ataxia-telangiectasia syndrome Familial cancer of breast Affected status: unknown Allele origin: unknown	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology Study: COAGS Accession: SCV002575016.1 First in ClinVar: Oct 01, 2022 Last updated: Oct 01, 2022	Comment: PS3_Moderate, PS4_Moderate (for AD cancers) or PM3_Strong (for AR ataxia-telangiectasia), PM2_Moderate, PP3_Supporting Number of individuals with the variant: 1
Pathogenic (Dec 09, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Familial cancer of breast Affected status: no Allele origin: germline	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV002762784.2 First in ClinVar: Dec 17, 2022 Last updated: Feb 25, 2023	Comment: PS3_MOD, PM3_VSTR , PM5
Likely pathogenic (Feb 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ataxia-telangiectasia syndrome Affected status: yes Allele origin: unknown	3billion Accession: SCV003842120.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Comment: 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 … (more) 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. (less) Clinical Features: Dystonic disorder (present) , Polyneuropathy (present) , Blepharospasm (present) , Torticollis (present) , Tremor (present)
Likely pathogenic (Sep 08, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ataxia-telangiectasia syndrome Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002024401.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Likely pathogenic (Oct 28, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Breast and/or ovarian cancer Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV004239538.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024
Pathogenic (Jan 29, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Ataxia-telangiectasia syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000260088.12 First in ClinVar: Jan 31, 2016 Last updated: Feb 14, 2024	Publications: PubMed (9) PubMed: 28492532‚ 2557216‚ 16864838‚ 19535770‚ 21354641‚ 21965147‚ 25957637‚ 26976419‚ 11805335 Comment: 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). … (more) 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. (less)
Pathogenic (Feb 02, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ataxia-telangiectasia syndrome Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004848893.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Comment: 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 … (more) 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. (less)
Likely pathogenic (Sep 12, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000187129.11 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Publications: PubMed (17) PubMed: 11805335‚ 19535770‚ 21354641‚ 21792198‚ 21965147‚ 22146522‚ 25122203‚ 25957637‚ 29478780‚ 29909963‚ 30322717‚ 30549301‚ 30579816‚ 30819809‚ 31050087‚ 32875559‚ 34445196 Comment: 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 … (more) 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. (less)
Pathogenic (Feb 01, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Ataxia-telangiectasia syndrome Affected status: no Allele origin: germline	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV005052017.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Pathogenic (Jun 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002497176.16 First in ClinVar: Apr 11, 2022 Last updated: Oct 20, 2024	Comment: ATM: PM3:Strong, PP1:Strong, PM2, PP3, PS3:Supporting, PS4:Supporting Number of individuals with the variant: 6
Pathogenic (Oct 07, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV001713587.1 First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021	Publications: PubMed (6) PubMed: 31050087‚ 30579816‚ 30549301‚ 30819809‚ 25572163‚ 19535770 Comment: PS3, PS4, PM2, PM3, PP3, PP4, PP5 Number of individuals with the variant: 1
Pathogenic (May 31, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Ataxia-telangiectasia syndrome Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002810822.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (May 31, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ataxia-telangiectasia syndrome (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	KCCC/NGS Laboratory, Kuwait Cancer Control Center Accession: SCV003927266.1 First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023	Comment: 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 … (more) 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. (less) Sex: male
Pathogenic (Nov 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002010779.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023
Pathogenic (Sep 10, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Department of Human Genetics, Hannover Medical School Accession: SCV005201118.1 First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024	Clinical Features: Healthy (present)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	Ataxia-telangiectasia syndrome (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin Accession: SCV005380271.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024	Clinical Features: Dysarthria (present) , Athetosis (present) , Incoordination (present) , Chiari type I malformation (present) , Parotid gland adenocarcinoma (present)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002036099.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001906005.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001955835.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (Feb 21, 2023)	no assertion criteria provided Method: clinical testing	Uterine corpus cancer Affected status: yes Allele origin: germline	CZECANCA consortium Accession: SCV003804338.1 First in ClinVar: Feb 25, 2023 Last updated: Feb 25, 2023	Number of individuals with the variant: 1 Ethnicity/Population group: Slavic Geographic origin: Czech Republic
Likely pathogenic (Jan 10, 2023)	no assertion criteria provided Method: clinical testing	Tip-toe gait Affected status: yes Allele origin: germline	Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino Accession: SCV004022483.2 First in ClinVar: Aug 05, 2023 Last updated: Jun 23, 2024	Publications: PubMed (1) PubMed: 37091313 Comment: Gait disorder Clinical Features: Delayed speech and language development (present) , Hyperlordosis (present) , Pes cavus (present) , Short 5th finger (present) , Pectus carinatum (present) Method: gene panel analysis
Pathogenic (Jul 31, 2024)	no assertion criteria provided Method: clinical testing	ATM-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004724027.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: 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 … (more) 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. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001740397.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Pathogenic (Sep 12, 2021)	no assertion criteria provided Method: clinical testing	Breast carcinoma (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences Accession: SCV001860286.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021	Sex: female
not provided (-)	no classification provided Method: literature only	Ataxia-telangiectasia syndrome Affected status: yes Allele origin: germline	GeneReviews Accession: SCV000328271.2 First in ClinVar: Jul 01, 2016 Last updated: Oct 01, 2022	Publications: PubMed (2) PubMed: 19605768‚ 19535770 BookShelf: NBK26468 BookShelf: NBK26468
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Comment:

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.

Comment:

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)

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
NGS-Panel Diagnosis Developed for the Differential Diagnosis of Idiopathic Toe Walking and Its Application for the Investigation of Possible Genetic Causes for the Gait Anomaly.	Pomarino D	Global medical genetics	2023	PMID: 37091313
Ataxia-Telangiectasia.	Adam MP	-	2023	PMID: 20301790
NGS in Hereditary Ataxia: When Rare Becomes Frequent.	Galatolo D	International journal of molecular sciences	2021	PMID: 34445196
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.	Breast Cancer Association Consortium	The New England journal of medicine	2021	PMID: 33471991
Mutations in ATM, NBN and BRCA2 predispose to aggressive prostate cancer in Poland.	Wokołorczyk D	International journal of cancer	2020	PMID: 32875559
Detection of Germline Mutations in a Cohort of 139 Patients with Bilateral Breast Cancer by Multi-Gene Panel Testing: Impact of Pathogenic Variants in Other Genes beyond BRCA1/2.	Fanale D	Cancers	2020	PMID: 32854451
Functional classification of ATM variants in ataxia-telangiectasia patients.	Fiévet A	Human mutation	2019	PMID: 31050087
Genotype-phenotype correlations in ataxia telangiectasia patients with ATM c.3576G>A and c.8147T>C mutations.	van Os NJH	Journal of medical genetics	2019	PMID: 30819809
Variant ataxia-telangiectasia with prominent camptocormia.	Paucar M	Parkinsonism & related disorders	2019	PMID: 30579816
Genotype, extrapyramidal features, and severity of variant ataxia-telangiectasia.	Schon K	Annals of neurology	2019	PMID: 30549301
Germline pathogenic variants identified in women with ovarian tumors.	Carter NJ	Gynecologic oncology	2018	PMID: 30322717
Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes.	Whitworth J	American journal of human genetics	2018	PMID: 29909963
Inherited DNA-Repair Defects in Colorectal Cancer.	AlDubayan SH	American journal of human genetics	2018	PMID: 29478780
Germline Mutations in DNA Repair Genes in Lung Adenocarcinoma.	Parry EM	Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer	2017	PMID: 28843361
Ataxia-telangiectasia: Immunodeficiency and survival.	van Os NJH	Clinical immunology (Orlando, Fla.)	2017	PMID: 28126470
Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer.	Tung N	Journal of clinical oncology : official journal of the American Society of Clinical Oncology	2016	PMID: 26976419
Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing.	Susswein LR	Genetics in medicine : official journal of the American College of Medical Genetics	2016	PMID: 26681312
Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome.	Yurgelun MB	Gastroenterology	2015	PMID: 25980754
Clinical variability in ataxia-telangiectasia.	Lohmann E	Journal of neurology	2015	PMID: 25957637
Novel ATM mutation in a German patient presenting as generalized dystonia without classical signs of ataxia-telangiectasia.	Kuhm C	Journal of neurology	2015	PMID: 25572163
The pleiotropic movement disorders phenotype of adult ataxia-telangiectasia.	Méneret A	Neurology	2014	PMID: 25122203
Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: a genotype-phenotype study.	Verhagen MM	Human mutation	2012	PMID: 22213089
Severe reaction to radiotherapy for breast cancer as the presenting feature of ataxia telangiectasia.	Byrd PJ	British journal of cancer	2012	PMID: 22146522
New mutations in the ATM gene and clinical data of 25 AT patients.	Demuth I	Neurogenetics	2011	PMID: 21965147
Lymphoid tumours and breast cancer in ataxia telangiectasia; substantial protective effect of residual ATM kinase activity against childhood tumours.	Reiman A	British journal of cancer	2011	PMID: 21792198
Functional characterization connects individual patient mutations in ataxia telangiectasia mutated (ATM) with dysfunction of specific DNA double-strand break-repair signaling pathways.	Keimling M	FASEB journal : official publication of the Federation of American Societies for Experimental Biology	2011	PMID: 21778326
Ataxia telangiectasia: the consequences of a delayed diagnosis.	Mandigers CM	Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology	2011	PMID: 21354641
Ataxia-telangiectasia: without ataxia or telangiectasia?	Saunders-Pullman RJ	Neurology	2009	PMID: 19605768
Clinical spectrum of ataxia-telangiectasia in adulthood.	Verhagen MM	Neurology	2009	PMID: 19535770
Distal spinal muscular atrophy as a major feature in adult-onset ataxia telangiectasia.	Hiel JA	Neurology	2006	PMID: 16864838
Functional consequences of sequence alterations in the ATM gene.	Lavin MF	DNA repair	2004	PMID: 15279808
Missense mutations but not allelic variants alter the function of ATM by dominant interference in patients with breast cancer.	Scott SP	Proceedings of the National Academy of Sciences of the United States of America	2002	PMID: 11805335
Comments on: "Two Routes for Renal 99mTc-DMSA Uptake into the Renal Cortical Tubular Cell".	de Lange MJ	European journal of nuclear medicine	1989	PMID: 2557216
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Text-mined citations for rs587782652 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

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

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Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587782652 ...