VCV000003036.59 - ClinVar

NM_000051.4(ATM):c.7327C>T (p.Arg2443Ter)

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.

(22)

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.7327C>T (p.Arg2443Ter)

Variation ID: 3036 Accession: VCV000003036.59

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q22.3 11: 108330233 (GRCh38) [ NCBI UCSC ] 11: 108200960 (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 20, 2024	Jul 9, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000051.4:c.7327C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000042.3:p.Arg2443Ter	nonsense
NM_001330368.2:c.641-21162G>A		intron variant
NM_001351110.2:c.*38+4987G>A		intron variant
NM_001351834.2:c.7327C>T	NP_001338763.1:p.Arg2443Ter	nonsense
NC_000011.10:g.108330233C>T
NC_000011.9:g.108200960C>T
NG_009830.1:g.112402C>T
NG_054724.1:g.144600G>A
LRG_135:g.112402C>T
LRG_135t1:c.7327C>T	LRG_135p1:p.Arg2443Ter

... more HGVS ... less HGVS

Protein change

R2443*

Other names

Canonical SPDI

NC_000011.10:108330232:C:T

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 0.00000

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA325513 OMIM: 607585.0019 dbSNP: rs121434220 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	10839	17439
C11orf65	-	-	-	GRCh38 GRCh37	3	6582

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.
Ataxia-telangiectasia syndrome	Pathogenic/Likely pathogenic (6)	criteria provided, multiple submitters, no conflicts	Jan 9, 2024	RCV000003175.31
Hereditary cancer-predisposing syndrome	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jul 9, 2024	RCV000220229.19
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Nov 22, 2023	RCV000484232.40
Familial cancer of breast	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	May 28, 2024	RCV001250440.17
Tip-toe gait	Pathogenic (1)	no assertion criteria provided	Jun 7, 2023	RCV003318492.9
Breast and/or ovarian cancer	Pathogenic (1)	no assertion criteria provided	Jun 11, 2019	RCV001270953.9
Carcinoma of pancreas	Pathogenic (1)	no assertion criteria provided	Mar 4, 2021	RCV001391206.9

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.
Pathogenic (Jul 14, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000805612.1 First in ClinVar: Sep 13, 2018 Last updated: Sep 13, 2018
Pathogenic (Apr 15, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: no Allele origin: germline	Division of Medical Genetics, University of Washington Study: CSER_CHARM Accession: SCV001424815.1 First in ClinVar: Jul 30, 2020 Last updated: Jul 30, 2020	Comment: The c.7327C>T variant creates a premature stop codon which is expected to lead to protein truncation or nonsense-mediated mRNA decay. Loss-of-function variants in ATM are … (more) The c.7327C>T variant creates a premature stop codon which is expected to lead to protein truncation or nonsense-mediated mRNA decay. Loss-of-function variants in ATM are considered pathogenic (Podralska 2014, Huang 2013). Women who are heterozygous for pathogenic variants in ATM have an increased risk for breast cancer. Men and women who are heterozygous for pathogenic variants in ATM may have an increased risk for pancreatic cancer. There are multiple reported individuals with breast, pancreatic and/or prostate cancer who are heterozygous for the c.7327C>T ATM variant (Leongamornlert 2014, Lhota 2016, Hu 2016). Individuals who are homozygous or compound heterozygous for pathogenic variants in ATM have Ataxia-telangiectasia. The c.7327C>T ATM variant has been reported in multiple individuals with Ataxia-telangiectasia who are compound heterozygous for a second ATM pathogenic variant (Soukupova 2011, Delia 2003, Li 2000, Sandoval 1999, Wright 1996). Thus, this variant is interpreted as pathogenic. (less)
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Unknown mechanism) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447181.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Cerebellar ataxia (present) Sex: male
Pathogenic (Jan 21, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ataxia-telangiectasia syndrome Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002022411.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jan 09, 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: SCV000260860.11 First in ClinVar: Jan 31, 2016 Last updated: Feb 14, 2024	Publications: PubMed (13) PubMed: 28492532‚ 23807571‚ 25614872‚ 8808599‚ 9887333‚ 10817650‚ 14586414‚ 21833744‚ 24556621‚ 26483394‚ 26822949‚ 14970866‚ 15101044 Comment: This sequence change creates a premature translational stop signal (p.Arg2443) in the ATM gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg2443) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is present in population databases (rs121434220, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia and prostate, breast, and pancreatic cancer (PMID: 8808599, 9887333, 10817650, 14586414, 21833744, 24556621, 26483394, 26822949). ClinVar contains an entry for this variant (Variation ID: 3036). Studies have shown that this premature translational stop signal alters ATM gene expression (PMID: 14970866, 15101044). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jan 31, 2024)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004932919.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Comment: This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Pathogenic (Jul 09, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. Accession: SCV005205780.1 First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024
Pathogenic (Feb 02, 2017)	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: SCV000694350.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017	Publications: PubMed (3) PubMed: 12673797‚ 12497634‚ 23454770 Comment: Variant summary: The ATM c.7327C>T (p.Arg2443X) variant results in a premature termination codon, predicted to cause absent ATM protein due to nonsense mediated decay, which … (more) Variant summary: The ATM c.7327C>T (p.Arg2443X) variant results in a premature termination codon, predicted to cause absent ATM protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This prediction has been confirmed by one study showing that the ATM protein is absent in cells from a patient who carries the variant of interest and a frameshift variant (Prodosmo_2013). Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.7517_7520delGAGA, c.8264_8268delATAAG). One in silico tool predicts a damaging outcome for this variant. This variant has been reported in multiple AT patients and is absent in 119996 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic. (less)
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: SCV001499653.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021
Pathogenic (May 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ataxia-telangiectasia syndrome Affected status: yes Allele origin: germline	3billion Accession: SCV002521262.1 First in ClinVar: Jun 05, 2022 Last updated: Jun 05, 2022	Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Stop-gained (nonsense): predicted to result in a … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000003036). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Cerebellar atrophy (present) , Elevated circulating alpha-fetoprotein concentration (present) , Enlarged cisterna magna (present) , Abnormal cerebellum morphology (present) , Nystagmus (present) , Polydactyly of … (more) Cerebellar atrophy (present) , Elevated circulating alpha-fetoprotein concentration (present) , Enlarged cisterna magna (present) , Abnormal cerebellum morphology (present) , Nystagmus (present) , Polydactyly of a biphalangeal thumb (present) , Hand polydactyly (present) , Intellectual disability, mild (present) , Exostoses (present) , Telangiectasia (present) , Gait ataxia (present) (less)
Likely pathogenic (Jul 19, 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: SCV000220525.2 First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022	Publications: PubMed (6) PubMed: 10817650‚ 24556621‚ 8808599‚ 9443866‚ 15101044‚ 9887333
Pathogenic (Feb 17, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000566496.5 First in ClinVar: Apr 27, 2017 Last updated: Mar 11, 2023	Comment: Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more) Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Observed as heterozygous in individuals with personal or family cancer history consistent with pathogenic variants in this gene referred for genetic testing at GeneDx and in published literature (Leongamornlert et al., 2014, Hu et al., 2016, Lhota et al., 2016, Resch et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 19440741, 21833744, 29922827, 24556621, 9443866, 25525159, 15101044, 12497634, 26822949, 28059096, 26483394, 28984303, 12673797, 10817650, 8808599, 9887333, 12697903, 17203191, 29522266, 30322717, 28888541, 33436325, 34680878, 30198223) (less)
Pathogenic (Nov 22, 2023)	criteria provided, single submitter (Hauer et al. (Genet Med. 2018)) Method: clinical testing	not provided (Unknown mechanism) Affected status: yes Allele origin: germline	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg Accession: SCV004167632.1 First in ClinVar: Nov 25, 2023 Last updated: Nov 25, 2023	Comment: This variant has been identified by standard clinical testing. female patient with triple-negative breast cancer Selected ACMG criteria: Pathogenic (I):PP5;PM2;PVS1 Number of individuals with the variant: 1
Pathogenic (Apr 18, 2022)	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: SCV000687767.4 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024	Publications: PubMed (8) PubMed: 10817650‚ 23454770‚ 26483394‚ 26822949‚ 33919281‚ 34337741‚ 34680878‚ 35078243 Comment: This variant changes 1 nucleotide in exon 50 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in … (more) This variant changes 1 nucleotide in exon 50 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast cancer (PMID: 26822949, 33919281, 34680878), pancreatic cancer (PMID: 26483394), and gastroesophageal junction adenocarcinoma (PMID: 35078243). This variant has also been observed in individuals affected with ataxia-telangiectasia in the homozygous state (PMID: 34337741) or the compound heterozygous state with a pathogenic truncation variant (PMID: 10817650, 23454770). This variant has been identified in 1/251068 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
Pathogenic (Apr 07, 2022)	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: SCV000273030.7 First in ClinVar: May 29, 2016 Last updated: May 01, 2024	Publications: PubMed (6) PubMed: 10817650‚ 15101044‚ 24556621‚ 26822949‚ 8808599‚ 9887333 Comment: The p.R2443* pathogenic mutation (also known as c.7327C>T), located in coding exon 49 of the ATM gene, results from a C to T substitution at … (more) The p.R2443* pathogenic mutation (also known as c.7327C>T), located in coding exon 49 of the ATM gene, results from a C to T substitution at nucleotide position 7327. This changes the amino acid from an arginine to a stop codon within coding exon 49. This mutation has been reported in numerous individuals with ataxia-telangiectasia (AT) (Wright J et al. Am. J. Hum. Genet. 1996 Oct;59:839-46; Gutiérrez-Enríquez S et al. Genes Chromosomes Cancer 2004 Jun;40:109-19; Sandoval N et al. Hum. Mol. Genet. 1999 Jan;8:69-79; Li A et al. Am. J. Med. Genet. 2000 May;92:170-7; Tariq H et al. J Clin Neurol 2018 Oct;14(4):498-504). This mutation has also been reported in a prostate cancer kindred in which it segregated with disease in an affected brother (Leongamornlert D et al. Br. J. Cancer 2014 Mar;110:1663-72) , in 2/325 high-risk Czech breast cancer patients (Lhota F et al. Clin. Genet. 2016 Oct;90:324-33), and 1/96 individuals with a personal and family history of pancreatic cancer (Hu C. et al. Cancer Epidemiol. Biomarkers Prev. 2016 Jan;25(1):207-11). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (Jan 11, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004206287.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (May 28, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast (Autosomal dominant inheritance) Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV003921051.4 First in ClinVar: May 06, 2023 Last updated: Oct 13, 2024	Comment: Criteria applied: PVS1,PM2_SUP,PM3_SUP Clinical Features: Breast carcinoma (present) Sex: female
Pathogenic (Dec 01, 2020)	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: SCV001246116.26 First in ClinVar: May 09, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 3
Pathogenic (Jan 01, 1999)	no assertion criteria provided Method: literature only	ATAXIA-TELANGIECTASIA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000023333.3 First in ClinVar: Apr 04, 2013 Last updated: Sep 18, 2016	Publications: PubMed (3) PubMed: 9443866‚ 9887333‚ 3338800 Comment on evidence: Telatar et al. (1998) found an arg2443-to-ter (R2443X) mutation in the ATM gene as the cause of ataxia-telangiectasia (AT; 208900) in African Americans. Sandoval et … (more) Telatar et al. (1998) found an arg2443-to-ter (R2443X) mutation in the ATM gene as the cause of ataxia-telangiectasia (AT; 208900) in African Americans. Sandoval et al. (1999) found the same mutation in 2 unrelated patients in Germany. The mutations may have arisen by independent mutation events, as the underlying nucleotide substitution affects the CpG dinucleotide, a known hotspot of mutations in general (Cooper and Youssoufian, 1988). The truncating mutation was caused by a C-to-T transition at nucleotide 7327 in exon 52. (less)
Pathogenic (Jun 11, 2019)	no assertion criteria provided Method: clinical testing	Breast and/or ovarian cancer Affected status: yes Allele origin: germline	CZECANCA consortium Accession: SCV001451757.1 First in ClinVar: Dec 24, 2020 Last updated: Dec 24, 2020	Publications: PubMed (1) PubMed: 32295079 Number of individuals with the variant: 1 Ethnicity/Population group: Slavic Geographic origin: Czech Republic
Pathogenic (Mar 04, 2021)	no assertion criteria provided Method: case-control	Carcinoma of pancreas Affected status: yes Allele origin: germline	CZECANCA consortium Accession: SCV001593149.1 First in ClinVar: May 14, 2021 Last updated: May 14, 2021	Number of individuals with the variant: 1 Ethnicity/Population group: Slavic Geographic origin: Czech Republic
Pathogenic (Jun 07, 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: SCV004022314.2 First in ClinVar: Aug 05, 2023 Last updated: Jun 23, 2024	Publications: PubMed (1) PubMed: 37091313 Comment: Gait disorder Clinical Features: Pes cavus (present) , Clinodactyly (present) , Lumbar hyperlordosis (present) , limited range of motion of upper ankle (present) Method: Gene panel analysis
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Comment:

The c.7327C>T variant creates a premature stop codon which is expected to lead to protein truncation or nonsense-mediated mRNA decay. Loss-of-function variants in ATM are considered pathogenic (Podralska 2014, Huang 2013). Women who are heterozygous for pathogenic variants in ATM have an increased risk for breast cancer. Men and women who are heterozygous for pathogenic variants in ATM may have an increased risk for pancreatic cancer. There are multiple reported individuals with breast, pancreatic and/or prostate cancer who are heterozygous for the c.7327C>T ATM variant (Leongamornlert 2014, Lhota 2016, Hu 2016). Individuals who are homozygous or compound heterozygous for pathogenic variants in ATM have Ataxia-telangiectasia. The c.7327C>T ATM variant has been reported in multiple individuals with Ataxia-telangiectasia who are compound heterozygous for a second ATM pathogenic variant (Soukupova 2011, Delia 2003, Li 2000, Sandoval 1999, Wright 1996). Thus, this variant is interpreted as pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Arg2443*) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is present in population databases (rs121434220, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia and prostate, breast, and pancreatic cancer (PMID: 8808599, 9887333, 10817650, 14586414, 21833744, 24556621, 26483394, 26822949). ClinVar contains an entry for this variant (Variation ID: 3036). Studies have shown that this premature translational stop signal alters ATM gene expression (PMID: 14970866, 15101044). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.

Comment:

Variant summary: The ATM c.7327C>T (p.Arg2443X) variant results in a premature termination codon, predicted to cause absent ATM protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This prediction has been confirmed by one study showing that the ATM protein is absent in cells from a patient who carries the variant of interest and a frameshift variant (Prodosmo_2013). Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.7517_7520delGAGA, c.8264_8268delATAAG). One in silico tool predicts a damaging outcome for this variant. This variant has been reported in multiple AT patients and is absent in 119996 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic.

Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000003036). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Observed as heterozygous in individuals with personal or family cancer history consistent with pathogenic variants in this gene referred for genetic testing at GeneDx and in published literature (Leongamornlert et al., 2014, Hu et al., 2016, Lhota et al., 2016, Resch et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 19440741, 21833744, 29922827, 24556621, 9443866, 25525159, 15101044, 12497634, 26822949, 28059096, 26483394, 28984303, 12673797, 10817650, 8808599, 9887333, 12697903, 17203191, 29522266, 30322717, 28888541, 33436325, 34680878, 30198223)

Comment:

This variant changes 1 nucleotide in exon 50 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast cancer (PMID: 26822949, 33919281, 34680878), pancreatic cancer (PMID: 26483394), and gastroesophageal junction adenocarcinoma (PMID: 35078243). This variant has also been observed in individuals affected with ataxia-telangiectasia in the homozygous state (PMID: 34337741) or the compound heterozygous state with a pathogenic truncation variant (PMID: 10817650, 23454770). This variant has been identified in 1/251068 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

Comment:

The p.R2443* pathogenic mutation (also known as c.7327C>T), located in coding exon 49 of the ATM gene, results from a C to T substitution at nucleotide position 7327. This changes the amino acid from an arginine to a stop codon within coding exon 49. This mutation has been reported in numerous individuals with ataxia-telangiectasia (AT) (Wright J et al. Am. J. Hum. Genet. 1996 Oct;59:839-46; Gutiérrez-Enríquez S et al. Genes Chromosomes Cancer 2004 Jun;40:109-19; Sandoval N et al. Hum. Mol. Genet. 1999 Jan;8:69-79; Li A et al. Am. J. Med. Genet. 2000 May;92:170-7; Tariq H et al. J Clin Neurol 2018 Oct;14(4):498-504). This mutation has also been reported in a prostate cancer kindred in which it segregated with disease in an affected brother (Leongamornlert D et al. Br. J. Cancer 2014 Mar;110:1663-72) , in 2/325 high-risk Czech breast cancer patients (Lhota F et al. Clin. Genet. 2016 Oct;90:324-33), and 1/96 individuals with a personal and family history of pancreatic cancer (Hu C. et al. Cancer Epidemiol. Biomarkers Prev. 2016 Jan;25(1):207-11). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

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
ATM Germline-Mutated Gastroesophageal Junction Adenocarcinomas: Clinical Descriptors, Molecular Characteristics, and Potential Therapeutic Implications.	El Jabbour T	Journal of the National Cancer Institute	2022	PMID: 35078243
The Importance of Extended Analysis Using Current Molecular Genetic Methods Based on the Example of a Cohort of 228 Patients with Hereditary Breast and Ovarian Cancer Syndrome.	Resch LD	Genes	2021	PMID: 34680878
The incidence and type of cancer in patients with ataxia-telangiectasia via a retrospective single-centre study.	Bakhtiar S	British journal of haematology	2021	PMID: 34337741
Clinicopathologic Profile of Breast Cancer in Germline ATM and CHEK2 Mutation Carriers.	Toss A	Genes	2021	PMID: 33919281
Hereditary truncating mutations of DNA repair and other genes in BRCA1/BRCA2/PALB2-negatively tested breast cancer patients.	Lhota F	Clinical genetics	2016	PMID: 26822949
Prevalence of Pathogenic Mutations in Cancer Predisposition Genes among Pancreatic Cancer Patients.	Hu C	Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology	2016	PMID: 26483394
Ten new ATM alterations in Polish patients with ataxia-telangiectasia.	Podralska MJ	Molecular genetics & genomic medicine	2014	PMID: 25614872
Frequent germline deleterious mutations in DNA repair genes in familial prostate cancer cases are associated with advanced disease.	Leongamornlert D	British journal of cancer	2014	PMID: 24556621
Twelve novel Atm mutations identified in Chinese ataxia telangiectasia patients.	Huang Y	Neuromolecular medicine	2013	PMID: 23807571
p53 centrosomal localization diagnoses ataxia-telangiectasia homozygotes and heterozygotes.	Prodosmo A	The Journal of clinical investigation	2013	PMID: 23454770
Characterisation of ATM mutations in Slavic Ataxia telangiectasia patients.	Soukupova J	Neuromolecular medicine	2011	PMID: 21833744
Functional consequences of ATM sequence variants for chromosomal radiosensitivity.	Gutiérrez-Enríquez S	Genes, chromosomes & cancer	2004	PMID: 15101044
Cellular responses to ionising radiation of AT heterozygotes: differences between missense and truncating mutation carriers.	Fernet M	British journal of cancer	2004	PMID: 14970866
DNA damage-induced cell-cycle phase regulation of p53 and p21waf1 in normal and ATM-defective cells.	Delia D	Oncogene	2003	PMID: 14586414
Designing and implementing quality control for multi-center screening of mutations in the ATM gene among women with breast cancer.	Bernstein JL	Human mutation	2003	PMID: 12673797
ATM mutations on distinct SNP and STR haplotypes in ataxia-telangiectasia patients of differing ethnicities reveal ancestral founder effects.	Campbell C	Human mutation	2003	PMID: 12497634
Mutations at the ataxia-telangiectasia locus and clinical phenotypes of A-T patients.	Li A	American journal of medical genetics	2000	PMID: 10817650
Characterization of ATM gene mutations in 66 ataxia telangiectasia families.	Sandoval N	Human molecular genetics	1999	PMID: 9887333
Ataxia-telangiectasia: identification and detection of founder-effect mutations in the ATM gene in ethnic populations.	Telatar M	American journal of human genetics	1998	PMID: 9443866
A high frequency of distinct ATM gene mutations in ataxia-telangiectasia.	Wright J	American journal of human genetics	1996	PMID: 8808599
The CpG dinucleotide and human genetic disease.	Cooper DN	Human genetics	1988	PMID: 3338800
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Text-mined citations for rs121434220 ...

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 03, 2024

ClinVar Genomic variation as it relates to human health

NM_000051.4(ATM):c.7327C>T (p.Arg2443Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121434220 ...