VCV000127414.81 - ClinVar

NM_000051.4(ATM):c.5932G>T (p.Glu1978Ter)

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.

(31)

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

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.5932G>T (p.Glu1978Ter)

Variation ID: 127414 Accession: VCV000127414.81

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q22.3 11: 108312424 (GRCh38) [ NCBI UCSC ] 11: 108183151 (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	Jan 31, 2016	Oct 26, 2024	May 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000051.4:c.5932G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000042.3:p.Glu1978Ter	nonsense
NM_001330368.2:c.641-3353C>A		intron variant
NM_001351110.2:c.*39-3353C>A		intron variant
NM_001351834.2:c.5932G>T	NP_001338763.1:p.Glu1978Ter	nonsense
NC_000011.10:g.108312424G>T
NC_000011.9:g.108183151G>T
NG_009830.1:g.94593G>T
NG_054724.1:g.162409C>A
LRG_135:g.94593G>T
LRG_135t1:c.5932G>T	LRG_135p1:p.Glu1978Ter

... more HGVS ... less HGVS

Protein change

E1978*

Other names

p.E1978*:GAA>TAA

Canonical SPDI

NC_000011.10:108312423:G: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.

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Exome Aggregation Consortium (ExAC) 0.00007

The Genome Aggregation Database (gnomAD) 0.00004

The Genome Aggregation Database (gnomAD), exomes 0.00004

Links

ClinGen: CA286910 dbSNP: rs587779852 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.
Hereditary cancer-predisposing syndrome	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 26, 2024	RCV000115219.22
Ataxia-telangiectasia syndrome	Pathogenic (8)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV000205725.30
not provided	Pathogenic (7)	criteria provided, multiple submitters, no conflicts	May 1, 2024	RCV000212035.43
Ataxia-telangiectasia syndrome Familial cancer of breast	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Mar 22, 2023	RCV000515323.13
Breast and/or ovarian cancer	Pathogenic (2)	criteria provided, single submitter	Jun 11, 2020	RCV001270929.11
Familial cancer of breast	Pathogenic (7)	criteria provided, multiple submitters, no conflicts	Feb 7, 2024	RCV001310112.18
Ataxia-telangiectasia syndrome Breast cancer, susceptibility to	Pathogenic (1)	criteria provided, single submitter	Dec 19, 2019	RCV001258122.9
ATM-related disorder	Pathogenic (1)	no assertion criteria provided	Jan 24, 2024	RCV004549559.2

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.
Pathogenic (Jan 09, 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: SCV000537636.4 First in ClinVar: Mar 24, 2017 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 10330348‚ 15880721‚ 16266405 Comment: This variant changes 1 nucleotide in exon 40 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 40 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 shown significant association with breast cancer in meta-analyses of multiple case-control studies (OR: 5.6, 95% CI: 1.3-21.4, p=0.01; PMID: 18807267) (OR: 4.56, 95% CI: 1.35-15.42, p=0.015; PMID: 21514219). This variant is a common cause of autosomal recessive ataxia-telangiectasia in Eastern Europe (PMID: 10330348, 15880721, 16266405). This variant has been identified in 11/251182 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 (Jan 25, 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: SCV000260557.11 First in ClinVar: Jan 31, 2016 Last updated: Feb 20, 2024	Publications: PubMed (9) PubMed: 28492532‚ 23807571‚ 25614872‚ 15880721‚ 16266405‚ 17124347‚ 18497957‚ 18807267‚ 19691550 Comment: This sequence change creates a premature translational stop signal (p.Glu1978) 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.Glu1978) 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 (rs587779852, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia and breast cancer (PMID: 15880721, 16266405, 17124347, 18497957, 18807267, 19691550, 25614872). ClinVar contains an entry for this variant (Variation ID: 127414). 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 26, 2024)	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: SCV000172771.9 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Publications: PubMed (17) PubMed: 10330348‚ 10817650‚ 10980530‚ 15880721‚ 16266405‚ 18807267‚ 19691550‚ 19781682‚ 25614872‚ 26380989‚ 26483394‚ 26506520‚ 27433846‚ 27449771‚ 28726808‚ 9443866‚ 9887333 Comment: The p.E1978* mutation (also known as c.5932G>T), located in coding exon 39 of the ATM gene, results from a G to T substitution at nucleotide … (more) The p.E1978* mutation (also known as c.5932G>T), located in coding exon 39 of the ATM gene, results from a G to T substitution at nucleotide position 5932. This changes the amino acid from a glutamate to a stop codon within exon 40. This alteration has been reported in multiple individuals with ataxia-telangiectasia from various ethnic backgrounds and is likely a Russian founder mutation (Li A et al. Am. J. Med. Genet. 2000 May;92(3):170-7; Birrell GW et al. Hum. Mutat. 2005 Jun;25(6):593; Mitui M et al. Ann. Hum. Genet. 2005 Nov;69(Pt 6):657-64; Podralska MJ et al. Mol. Genet. Genomic Med. 2014 Nov;2(6):504-11). In addition, p.E1978* has been described as a breast cancer susceptibility allele of Eastern European origin (Bogdanova N et al. Breast Cancer Res. Treat. 2009 Nov;118(1):207-11). It was also seen in a patient with prostate cancer with a Gleason score of 9 (Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375(5):443-53) and in cohorts of pancreatic cancer patients (Chaffee KG et al. Genet Med. 2018 01;20:119-127; Hu C et al. Cancer Epidemiol Biomarkers Prev. 2016 Jan;25:207-11). This mutation was shown to cause skipping of coding exon 39 (reported as exon 42), as well as a premature truncation in a subset of ATM transcripts (Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun;64(6):1617-31). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by aberrant splicing, premature protein truncation, or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
Pathogenic (Dec 19, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Susceptibility to breast cancer Ataxia-telangiectasia Affected status: unknown Allele origin: germline	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine Accession: SCV001434995.1 First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020	Comment: This c.5932G>T (p.Glu1978Ter) variant in exon 41 of the ATM gene creates a premature translational stop signal and is predicted to result in loss of … (more) This c.5932G>T (p.Glu1978Ter) variant in exon 41 of the ATM gene creates a premature translational stop signal and is predicted to result in loss of function through nonsense-mediated mRNA decay or by producing a truncated protein. This variant is present in population databases (rs587779852, gnomAD 0.004379%). This variant has been reported in several individuals affected with ataxia-telangiectasia (PMID: 15880721, 16266405, 17124347, 18497957, 19691550, 25614872) and breast cancer (PMID: 18807267). It has been found to be a prevalent ATM mutation in Eastern Europe (PMID: 15880721, 16266405, 18807267). Experimental studies indicate that this nonsense change leads to out-of-frame skipping of exon 41 (PMID: 10330348, 24451234). Therefore, this variant is classified 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: SCV001447589.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Cerebellar ataxia (present) Sex: female
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: SCV001499652.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021
Pathogenic (Jun 11, 2020)	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: SCV002042692.1 First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022
Pathogenic (Feb 23, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000149128.17 First in ClinVar: May 17, 2014 Last updated: Mar 04, 2023	Comment: Predicted to result in protein truncation or nonsense mediated decay, either by premature stop or splice defect, in a gene for which loss-of-function is a … (more) Predicted to result in protein truncation or nonsense mediated decay, either by premature stop or splice defect, in a gene for which loss-of-function is a known mechanism of disease (Telatar 1998, Teraoka 1999, Mitui 2005, Mort 2014); Observed in the heterozygous state in individuals with ATM-related cancers (Soukupova 2008, Huang 2015, Hu 2016, Pritchard 2016, Yang 2016, Decker 2017, Brand 2018, Isaacsson Velho 2018, Penkert 2018); Case control studies suggest this variant is associated with breast cancer (Bogdanova 2009, Zhang 2011); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26483394, 26681312, 21514219, 24451234, 10817650, 16266405, 9872980, 8808599, 10330348, 19781682, 9443866, 18807267, 18497957, 26380989, 26506520, 25525159, 27112364, 10980530, 27449771, 27433846, 28779002, 29368341, 29625052, 30322717, 30113427, 30549301, 30067863, 30086788, 34426522, 32295079, 15880721, 33077847, 31589614, 33436325, 33726816, 32441320, 27535533) (less)
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: SCV003841686.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Publications: PubMed (1) PubMed: 9443866 Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). This variant was predicted to result in … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). This variant was 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: VCV000127414 / PMID: 9443866). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Cerebellar ataxia (present)
Pathogenic (Apr 08, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: case-control	Ataxia-telangiectasia syndrome Affected status: yes Allele origin: germline	Cancer Variant Interpretation Group UK, Institute of Cancer Research, London Accession: SCV003933670.1 First in ClinVar: Jul 01, 2023 Last updated: Jul 01, 2023	Comment: Data included in classification: Truncating nonsense variant with frameshift (https://doi.org/10.1007/s10549-008-0189-9) (PVS1_vstr) Bogdanova et al 2008 (https://doi.org/10.1007/s10549-008-0189-9) Mantel–Haenszel Odds Ratio (OR): 5.6, 95% CI: 1.3–21.4, P … (more) Data included in classification: Truncating nonsense variant with frameshift (https://doi.org/10.1007/s10549-008-0189-9) (PVS1_vstr) Bogdanova et al 2008 (https://doi.org/10.1007/s10549-008-0189-9) Mantel–Haenszel Odds Ratio (OR): 5.6, 95% CI: 1.3–21.4, P = 0.01 - p ≤0.05 and OR is above 2 (PS4_str) Termination at a codon prior to p.Arg3047 (PM5_sup) Identified in 8/32 alleles in probands with ataxia telangiectasia (https://doi.org/10.1002/humu.9341) Observations in multiple ataxia telangiectasia cases (PMID: 15880721, 16266405, 17124347, 18807267, 19691550, 25614872, 18497957) (PM3_vstr) Data not included in classification: Multiple classification as pathogenic in ClinVar Allele frequency in Non-Finnish Europeans (NFE), gnomAD v2.1 Jan 2019: 5/102582 (0.005%). Variant frequency is at a frequency of ≥0.001%. (less) Number of individuals with the variant: 20 Clinical Features: Breast carcinoma (present) Comment on evidence: Observed in 20/6412 breast cancer cases and 2/3608 controls
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: SCV002010802.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023
Pathogenic (Aug 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV004027248.1 First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023
Pathogenic (May 10, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ataxia-telangiectasia syndrome Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002022488.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
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: SCV005052016.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Pathogenic (Feb 07, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004208790.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Jan 15, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005199613.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Jul 14, 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: SCV000694312.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017	Publications: PubMed (4) PubMed: 15880721‚ 18807267‚ 25614872‚ 16266405 Comment: Variant summary: The ATM c.5932G>T (p.Glu1978X) variant results in a premature termination codon, predicted to cause a truncated or absent ATM protein due to nonsense … (more) Variant summary: The ATM c.5932G>T (p.Glu1978X) variant results in a premature termination codon, predicted to cause a truncated or absent ATM protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., c.7327C>T [p.Arg2443X], c.7517_7520delGAGA [p.Arg2506fsX3], and c.7913G>A [p.Trp2638X]). One in silico tool predicts a damaging outcome for this variant. This variant was found in the control database ExAC and control cohorts reported in the literature at a frequency of 0.0000779 (10/128320 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0039528). The variant has been found in homozygosity and compound heterozygosity in numerous patients and families with ataxia-telangiectasia (Podralska_MGGM_2014; Birrell_HM_2005). Additionally, a large case-control study showed that the variant is enriched in heterozygous breast cancer patients in Eastern European populations (Odds Ratio = 5.6; 95% CI = 1.323.4; p = 0.01; Bogdanova_BCRT_2009). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic for both ataxia-telangiectasia and hereditary cancer. Taken together, this variant is classified as pathogenic. (less)
Pathogenic (Oct 11, 2021)	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: SCV002064361.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022	Comment: DNA sequence analysis of the ATM gene demonstrated a sequence change, c.5932G>T, in exon 40 that results in the creation of a premature stop codon … (more) DNA sequence analysis of the ATM gene demonstrated a sequence change, c.5932G>T, in exon 40 that results in the creation of a premature stop codon at amino acid position 1978, p.Glu1978. This variant is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated ATM protein with potentially abnormal function. The p.Glu1978 change has been described in the gnomAD database with a frequency of 0.009% in the European sub-population (dbSNP rs587779852) and is a prevalent ATM variant in the Eastern European population (PMIDs: 15880721, 16266405, 18807267). This sequence change has been described in several individuals with ataxia-telangiectasia and breast cancer (PMIDs: 26380989, 30549301, 15880721, 16266405, 25614872, 17124347, 19691550, 18807267, 28779002, 30086788). The p.Glu1978* change has also been observed in individuals with pancreatic cancer, ovarian cancer, gastric cancer, and prostate cancer (PMIDs: 30067863, 27449771, 30322717, 26506520, 29368341). Functional studies have demonstrated skipping of exon 40 in the presence of this sequence change (PMIDs: 9443866, 10330348, 24451234). These collective evidences indicate that this is a pathogenic sequence change. (less)
Pathogenic (Mar 11, 2016)	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015)) Method: clinical testing	Ataxia-telangiectasia syndrome Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000485199.2 First in ClinVar: Jan 31, 2016 Last updated: Dec 24, 2022
Pathogenic (May 10, 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: SCV000611165.2 First in ClinVar: Nov 11, 2017 Last updated: Dec 31, 2022
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: SCV002762777.2 First in ClinVar: Dec 17, 2022 Last updated: Feb 25, 2023	Comment: PVS1, PS3_MOD, PM3_VSTR
Pathogenic (Apr 20, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Affected status: yes Allele origin: germline	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein Accession: SCV003807006.1 First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023	Comment: ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 strong, PM2 moderated, PM3 moderated Number of individuals with the variant: 1 Clinical Features: Breast carcinoma (present) Geographic origin: Brazil Method: Paired-end whole-genome sequencing
Pathogenic (Dec 23, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV004175649.1 First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023
Pathogenic (Jan 26, 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: SCV004931115.1 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 (May 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: SCV001246111.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: ATM: PVS1, PM2, PS4:Moderate, PS3:Supporting Number of individuals with the variant: 10
Pathogenic (Mar 22, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ataxia-telangiectasia syndrome Familial cancer of breast Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: maternal	Institute of Immunology and Genetics Kaiserslautern Accession: SCV005382120.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024	Comment: ACMG Criteria: PVS1, PS3, PS4, PP5; Variant was found in heterozygous state.
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Ataxia-telangiectasia Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001457398.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Pathogenic (Jan 24, 2024)	no assertion criteria provided Method: clinical testing	ATM-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000805589.3 First in ClinVar: Sep 13, 2018 Last updated: Oct 08, 2024	Comment: The ATM c.5932G>T variant is predicted to result in premature protein termination (p.Glu1978). This variant has previously been reported by several studies in individuals with … (more) The ATM c.5932G>T variant is predicted to result in premature protein termination (p.Glu1978). This variant has previously been reported by several studies in individuals with ataxia telangiectasia (Telatar et al 1998. PubMed ID: 9443866; Birrell et al. 2005. PubMed ID: 15880721; Mitui et al. 2005. PubMed ID: 16266405). This variant is also associated with breast cancer susceptibility (Bogdanova et al. 2009. PubMed ID: 18807267). This variant is particularly prevalent in families with a history of ataxia telangiectasia and who are of Eastern European decent (specifically Polish and Russian) (Mitui et al. 2005. PubMed ID: 16266405; Birrell et al. 2005. PubMed ID: 15880721). This variant is reported in 0.0088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127414/?new_evidence=true). Nonsense variants in ATM are expected to be pathogenic. This variant is interpreted as pathogenic. (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: SCV001451733.1 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 (Aug 26, 2022)	no assertion criteria provided Method: clinical testing	Familial cancer of breast Affected status: yes Allele origin: germline	BRCAlab, Lund University Accession: SCV002588922.1 First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023
not provided (-)	no classification provided Method: phenotyping only	Ataxia-telangiectasia syndrome Familial cancer of breast Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: yes Allele origin: maternal	GenomeConnect - Invitae Patient Insights Network Accession: SCV004228579.1 First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024	Comment: Variant interpreted as Pathogenic and reported on 08-07-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided … (more) Variant interpreted as Pathogenic and reported on 08-07-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less) Clinical Features: Abnormal skull morphology (present) , Autoimmunity (present) , Immunodeficiency (present) , Recurrent infections (present) , Abnormality of coordination (present) , Pregnancy history (present) Indication for testing: Diagnostic Age: 0-9 years Sex: female Method: Gene Panel Sequencing Testing laboratory: Invitae Date variant was reported to submitter: 2019-08-07 Testing laboratory interpretation: Pathogenic
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Comment:

This variant changes 1 nucleotide in exon 40 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 shown significant association with breast cancer in meta-analyses of multiple case-control studies (OR: 5.6, 95% CI: 1.3-21.4, p=0.01; PMID: 18807267) (OR: 4.56, 95% CI: 1.35-15.42, p=0.015; PMID: 21514219). This variant is a common cause of autosomal recessive ataxia-telangiectasia in Eastern Europe (PMID: 10330348, 15880721, 16266405). This variant has been identified in 11/251182 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:

This sequence change creates a premature translational stop signal (p.Glu1978*) 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 (rs587779852, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia and breast cancer (PMID: 15880721, 16266405, 17124347, 18497957, 18807267, 19691550, 25614872). ClinVar contains an entry for this variant (Variation ID: 127414). 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:

The p.E1978* mutation (also known as c.5932G>T), located in coding exon 39 of the ATM gene, results from a G to T substitution at nucleotide position 5932. This changes the amino acid from a glutamate to a stop codon within exon 40. This alteration has been reported in multiple individuals with ataxia-telangiectasia from various ethnic backgrounds and is likely a Russian founder mutation (Li A et al. Am. J. Med. Genet. 2000 May;92(3):170-7; Birrell GW et al. Hum. Mutat. 2005 Jun;25(6):593; Mitui M et al. Ann. Hum. Genet. 2005 Nov;69(Pt 6):657-64; Podralska MJ et al. Mol. Genet. Genomic Med. 2014 Nov;2(6):504-11). In addition, p.E1978* has been described as a breast cancer susceptibility allele of Eastern European origin (Bogdanova N et al. Breast Cancer Res. Treat. 2009 Nov;118(1):207-11). It was also seen in a patient with prostate cancer with a Gleason score of 9 (Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375(5):443-53) and in cohorts of pancreatic cancer patients (Chaffee KG et al. Genet Med. 2018 01;20:119-127; Hu C et al. Cancer Epidemiol Biomarkers Prev. 2016 Jan;25:207-11). This mutation was shown to cause skipping of coding exon 39 (reported as exon 42), as well as a premature truncation in a subset of ATM transcripts (Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun;64(6):1617-31). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by aberrant splicing, premature protein truncation, or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

Comment:

This c.5932G>T (p.Glu1978Ter) variant in exon 41 of the ATM gene creates a premature translational stop signal and is predicted to result in loss of function through nonsense-mediated mRNA decay or by producing a truncated protein. This variant is present in population databases (rs587779852, gnomAD 0.004379%). This variant has been reported in several individuals affected with ataxia-telangiectasia (PMID: 15880721, 16266405, 17124347, 18497957, 19691550, 25614872) and breast cancer (PMID: 18807267). It has been found to be a prevalent ATM mutation in Eastern Europe (PMID: 15880721, 16266405, 18807267). Experimental studies indicate that this nonsense change leads to out-of-frame skipping of exon 41 (PMID: 10330348, 24451234). Therefore, this variant is classified as pathogenic.

Comment:

Predicted to result in protein truncation or nonsense mediated decay, either by premature stop or splice defect, in a gene for which loss-of-function is a known mechanism of disease (Telatar 1998, Teraoka 1999, Mitui 2005, Mort 2014); Observed in the heterozygous state in individuals with ATM-related cancers (Soukupova 2008, Huang 2015, Hu 2016, Pritchard 2016, Yang 2016, Decker 2017, Brand 2018, Isaacsson Velho 2018, Penkert 2018); Case control studies suggest this variant is associated with breast cancer (Bogdanova 2009, Zhang 2011); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26483394, 26681312, 21514219, 24451234, 10817650, 16266405, 9872980, 8808599, 10330348, 19781682, 9443866, 18807267, 18497957, 26380989, 26506520, 25525159, 27112364, 10980530, 27449771, 27433846, 28779002, 29368341, 29625052, 30322717, 30113427, 30549301, 30067863, 30086788, 34426522, 32295079, 15880721, 33077847, 31589614, 33436325, 33726816, 32441320, 27535533)

Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). This variant was 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: VCV000127414 / PMID: 9443866). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

Data included in classification: Truncating nonsense variant with frameshift (https://doi.org/10.1007/s10549-008-0189-9) (PVS1_vstr) Bogdanova et al 2008 (https://doi.org/10.1007/s10549-008-0189-9) Mantel–Haenszel Odds Ratio (OR): 5.6, 95% CI: 1.3–21.4, P = 0.01 - p ≤0.05 and OR is above 2 (PS4_str) Termination at a codon prior to p.Arg3047 (PM5_sup) Identified in 8/32 alleles in probands with ataxia telangiectasia (https://doi.org/10.1002/humu.9341) Observations in multiple ataxia telangiectasia cases (PMID: 15880721, 16266405, 17124347, 18807267, 19691550, 25614872, 18497957) (PM3_vstr) Data not included in classification: Multiple classification as pathogenic in ClinVar Allele frequency in Non-Finnish Europeans (NFE), gnomAD v2.1 Jan 2019: 5/102582 (0.005%). Variant frequency is at a frequency of ≥0.001%.

Comment:

Variant summary: The ATM c.5932G>T (p.Glu1978X) variant results in a premature termination codon, predicted to cause a truncated or absent ATM protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., c.7327C>T [p.Arg2443X], c.7517_7520delGAGA [p.Arg2506fsX3], and c.7913G>A [p.Trp2638X]). One in silico tool predicts a damaging outcome for this variant. This variant was found in the control database ExAC and control cohorts reported in the literature at a frequency of 0.0000779 (10/128320 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0039528). The variant has been found in homozygosity and compound heterozygosity in numerous patients and families with ataxia-telangiectasia (Podralska_MGGM_2014; Birrell_HM_2005). Additionally, a large case-control study showed that the variant is enriched in heterozygous breast cancer patients in Eastern European populations (Odds Ratio = 5.6; 95% CI = 1.323.4; p = 0.01; Bogdanova_BCRT_2009). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic for both ataxia-telangiectasia and hereditary cancer. Taken together, this variant is classified as pathogenic.

Comment:

DNA sequence analysis of the ATM gene demonstrated a sequence change, c.5932G>T, in exon 40 that results in the creation of a premature stop codon at amino acid position 1978, p.Glu1978*. This variant is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated ATM protein with potentially abnormal function. The p.Glu1978* change has been described in the gnomAD database with a frequency of 0.009% in the European sub-population (dbSNP rs587779852) and is a prevalent ATM variant in the Eastern European population (PMIDs: 15880721, 16266405, 18807267). This sequence change has been described in several individuals with ataxia-telangiectasia and breast cancer (PMIDs: 26380989, 30549301, 15880721, 16266405, 25614872, 17124347, 19691550, 18807267, 28779002, 30086788). The p.Glu1978* change has also been observed in individuals with pancreatic cancer, ovarian cancer, gastric cancer, and prostate cancer (PMIDs: 30067863, 27449771, 30322717, 26506520, 29368341). Functional studies have demonstrated skipping of exon 40 in the presence of this sequence change (PMIDs: 9443866, 10330348, 24451234). These collective evidences indicate that this is a pathogenic sequence change.

Comment:

The ATM c.5932G>T variant is predicted to result in premature protein termination (p.Glu1978*). This variant has previously been reported by several studies in individuals with ataxia telangiectasia (Telatar et al 1998. PubMed ID: 9443866; Birrell et al. 2005. PubMed ID: 15880721; Mitui et al. 2005. PubMed ID: 16266405). This variant is also associated with breast cancer susceptibility (Bogdanova et al. 2009. PubMed ID: 18807267). This variant is particularly prevalent in families with a history of ataxia telangiectasia and who are of Eastern European decent (specifically Polish and Russian) (Mitui et al. 2005. PubMed ID: 16266405; Birrell et al. 2005. PubMed ID: 15880721). This variant is reported in 0.0088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127414/?new_evidence=true). Nonsense variants in ATM are expected to be pathogenic. This variant is interpreted as pathogenic.

Comment:

Variant interpreted as Pathogenic and reported on 08-07-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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
Prevalence of germ-line mutations in cancer genes among pancreatic cancer patients with a positive family history.	Chaffee KG	Genetics in medicine : official journal of the American College of Medical Genetics	2018	PMID: 28726808
Multiple rare variants in high-risk pancreatic cancer-related genes may increase risk for pancreatic cancer in a subset of patients with and without germline CDKN2A mutations.	Yang XR	Human genetics	2016	PMID: 27449771
Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer.	Pritchard CC	The New England journal of medicine	2016	PMID: 27433846
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
Prevalence of deleterious ATM germline mutations in gastric cancer patients.	Huang DS	Oncotarget	2015	PMID: 26506520
Ataxia-Telangiectasia Presenting as Cerebral Palsy and Recurrent Wheezing: A Case Report.	Navratil M	The American journal of case reports	2015	PMID: 26380989
Ten new ATM alterations in Polish patients with ataxia-telangiectasia.	Podralska MJ	Molecular genetics & genomic medicine	2014	PMID: 25614872
Twelve novel Atm mutations identified in Chinese ataxia telangiectasia patients.	Huang Y	Neuromolecular medicine	2013	PMID: 23807571
Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer.	Tavtigian SV	American journal of human genetics	2009	PMID: 19781682
Founder effects for ATM gene mutations in Italian Ataxia Telangiectasia families.	Chessa L	Annals of human genetics	2009	PMID: 19691550
A nonsense mutation (E1978X) in the ATM gene is associated with breast cancer.	Bogdanova N	Breast cancer research and treatment	2009	PMID: 18807267
Contribution of mutations in ATM to breast cancer development in the Czech population.	Soukupova J	Oncology reports	2008	PMID: 18497957
DHPLC screening of ATM gene in Italian patients affected by ataxia-telangiectasia: fourteen novel ATM mutations.	Magliozzi M	Disease markers	2006	PMID: 17124347
ATM gene founder haplotypes and associated mutations in Polish families with ataxia-telangiectasia.	Mitui M	Annals of human genetics	2005	PMID: 16266405
ATM mutations, haplotype analysis, and immunological status of Russian patients with ataxia telangiectasia.	Birrell GW	Human mutation	2005	PMID: 15880721
Characterization of ATM mutations in 41 Nordic families with ataxia telangiectasia.	Laake K	Human mutation	2000	PMID: 10980530
Mutations at the ataxia-telangiectasia locus and clinical phenotypes of A-T patients.	Li A	American journal of medical genetics	2000	PMID: 10817650
Splicing defects in the ataxia-telangiectasia gene, ATM: underlying mutations and consequences.	Teraoka SN	American journal of human genetics	1999	PMID: 10330348
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
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Text-mined citations for rs587779852 ...

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.5932G>T (p.Glu1978Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587779852 ...