This sequence change creates a premature translational stop signal (p.Val1268*) 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 (rs765158119, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (A-T), and breast cancer (PMID: 8755918, 9887333, 10330348, 10864201, 11606401, 12815592, 16832357, 18384426, 21787400, 23585524, 25077176, 25614872). It is commonly reported in individuals of British Isles ancestry (PMID: 8755918, 9463314, 9887333, 10330348, 10864201, 11606401, 12815592, 16832357, 18384426, 21787400, 22585167, 23585524, 25077176, 25614872). This variant is also known as c.3801delG. ClinVar contains an entry for this variant (Variation ID: 127374). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000051.4(ATM):c.3802del (p.Glu1267_Val1268insTer)
Germline
Classification
Help
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.
(35)
Help
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
35
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.3802del (p.Glu1267_Val1268insTer)
Variation ID: 127374 Accession: VCV000127374.69
- Type and length
-
Deletion, 1 bp
- Location
-
Cytogenetic: 11q22.3 11: 108284281 (GRCh38) [ NCBI UCSC ] 11: 108155008 (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 Jul 1, 2016 Oct 20, 2024 Mar 11, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000051.4:c.3802del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000042.3:p.Glu1267_Val1268insTer nonsense NM_000051.4:c.3802delG MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000051.3:c.3802delG NM_001351834.2:c.3802del NP_001338763.1:p.Glu1267_Val1268insTer nonsense NC_000011.10:g.108284282del NC_000011.9:g.108155009del NG_009830.1:g.66451del LRG_135:g.66451del - Protein change
- -
- Other names
- -
- Canonical SPDI
- NC_000011.10:108284280:GG:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe 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.
- -
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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 |
10842 | 17443 | |
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. |
|---|---|---|---|---|
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 13, 2023 | RCV000115179.21 | |
| Pathogenic (9) |
criteria provided, multiple submitters, no conflicts
|
Jan 28, 2024 | RCV000198788.25 | |
| Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Mar 11, 2024 | RCV001310114.13 | |
| Pathogenic (10) |
criteria provided, multiple submitters, no conflicts
|
Feb 6, 2024 | RCV000212002.37 | |
| Pathogenic (1) |
no assertion criteria provided
|
Aug 19, 2021 | RCV001572625.4 | |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV001356822.5 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 3, 2020 | RCV001798314.5 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Jul 13, 2021 | RCV002490772.2 | |
|
ATM-related cancer predisposition syndrome
|
Pathogenic (1) |
criteria provided, single submitter
|
Apr 28, 2023 | RCV003314561.3 |
|
ATM-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Jun 3, 2024 | RCV004549548.3 |
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 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: no
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440815.1
First in ClinVar: Oct 30, 2020 Last updated: Oct 30, 2020 |
|
|
|
Pathogenic
(Apr 02, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: yes
Allele origin:
germline
|
Department of Molecular Diagnostics, Institute of Oncology Ljubljana
Accession: SCV001499656.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
|
|
|
Pathogenic
(Nov 03, 2020)
|
criteria provided, single submitter
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: SCV002042158.1
First in ClinVar: Dec 29, 2021 Last updated: Dec 29, 2021 |
|
|
|
Pathogenic
(Jun 13, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002580935.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PVS1, PM3_STR, PS4_MOD, PM2_SUP
|
Number of individuals with the variant: 2
Sex: male
|
|
|
Pathogenic
(Jan 28, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000253740.13
First in ClinVar: Oct 11, 2015 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Val1268*) 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.Val1268*) 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 (rs765158119, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (A-T), and breast cancer (PMID: 8755918, 9887333, 10330348, 10864201, 11606401, 12815592, 16832357, 18384426, 21787400, 23585524, 25077176, 25614872). It is commonly reported in individuals of British Isles ancestry (PMID: 8755918, 9463314, 9887333, 10330348, 10864201, 11606401, 12815592, 16832357, 18384426, 21787400, 22585167, 23585524, 25077176, 25614872). This variant is also known as c.3801delG. ClinVar contains an entry for this variant (Variation ID: 127374). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Mar 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000682163.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This variant deletes 1 nucleotide in exon 26 of the ATM gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more)
This variant deletes 1 nucleotide in exon 26 of the ATM gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in the homozygous or compound heterozygous state with an additional pathogenic ATM variant in individuals affected with ataxia-telangiectasia (PMID: 8755918, 9887333, 10864201, 21965147, 25077176, 25614872, 27664052, 34337741). This variant has also been reported in individuals affected with breast cancer (PMID: 16832357, 18384426, 21445571, 21787400), pancreatic cancer (PMID: 22585167), prostate cancer (PMID: 27433846, 33436325), and gastroesophageal junction adenocarcinoma (PMID: 35078243). This variant has been identified in 11/282542 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
(Mar 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004206203.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Jan 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000149088.15
First in ClinVar: May 17, 2014 Last updated: Sep 16, 2024 |
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 … (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 in the heterozygous state in individuals with ATM-related cancers (PMID: 11606401, 18384426, 19781682, 22585167, 27433846, 30306255, 29915322, 29961768); 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; Also known as 3801delG; This variant is associated with the following publications: (PMID: 16832357, 25077176, 10330348, 15039971, 29478780, 17124347, 30772474, 32866655, 34637943, 32818697, 30257646, 29922827, 28888541, 34758253, 35047863, 23585524, 19781682, 12497634, 25614872, 25037873, 8755918, 22585167, 26786923, 21787400, 27664052, 10864201, 9463314, 11606401, 18384426, 27433846, 27484032, 21445571, 21965147, 28652578, 28691344, 30306255, 9887333, 12815592, 28779002, 21665257, 26182300, 29915322, 29961768, 30303537, 29625052, 26689913, 26896183, 31589614, 32853339, 33436325, 32338768, 35626031, 33758026, 34445196, 36139606, 35264596, 33804961) (less)
|
|
|
Pathogenic
(Jan 20, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Athena Diagnostics
Accession: SCV000840935.1
First in ClinVar: Oct 19, 2018 Last updated: Oct 19, 2018 |
|
|
|
Pathogenic
(Jul 03, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000916584.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: ATM c.3802delG (p.Val1268X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: ATM c.3802delG (p.Val1268X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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., p.Arg1466X and p.Ser1905fsX25). The variant allele was found at a frequency of 4e-05 in 276948 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (4e-05 vs 0.004), allowing no conclusion about variant significance. c.3802delG has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia as both a homozygous and compound heterozygous allele, indicating the variant is very likely to be associated with disease. At least one publication reports functional data indicating the variant significantly impairs protein expression and kinase activity in patient cells (Carranza_2017). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Jan 04, 2021)
|
criteria provided, single submitter
Method: research
|
Ataxia-telangiectasia syndrome
Affected status: yes
Allele origin:
inherited
|
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris
Accession: SCV001519103.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
|
|
|
Pathogenic
(Jun 17, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
|
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group
Accession: SCV001911458.1
First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
Comment:
The c.3802del (p.Val1268*) variant generates a stop codon that is predicted to result in a truncated or absent protein, due to nonsense mediated decay (NMD) … (more)
The c.3802del (p.Val1268*) variant generates a stop codon that is predicted to result in a truncated or absent protein, due to nonsense mediated decay (NMD) (PVS1). It has an allele frequency of 0.0034%, (9/268,016 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.0086%, (3/35,074 alleles) in the the Latino / Admixed American subpopulation (no population frequency criterion met; http://gnomad.broadinstitute.org). It has been reported in at least eighteen ataxia-telangiectasia probands in homozygosis or together with (likely) pathogenic variants, which awards 4 points to this variant as per ClinGen SVI Recommendation for in trans Criterion (PM3_VeryStrong; PMID: 27664052, 10330348, 12815592, 21665257, 21965147, 8755918, 9887333). Moreover, lymphoblastoid cell lines of patients carrying this variant have been reported to have residual or absent ATM protein expression, no detectable ATM p.Ser1981 autophosphorylation, weak transphosphorylation activity of two substrates and intermediate or high radiosensitivity (PS3; PMID: 10864201, 27664052, 25077176). Therefore, this variant meets criteria to be classified as pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PVS1 + PM3_VeryStrong + PS3 (PMID: 33280026). (less)
Observation 1:
Clinical Features:
Breast carcinoma (present) , Pancreatic adenocarcinoma (present)
Indication for testing: Familial pancreatic carcinoma
Ethnicity/Population group: European caucasoid
Testing laboratory: Molecular Diagnostics Laboratory, Hereditary Cancer Program, Catalan Institute of Oncology, Granvia de l’Hospitalet 199-203, 08908 L’Hospitalet de Llobregat, Barcelona, Spain
Observation 2:
Clinical Features:
Breast carcinoma (present)
Indication for testing: Breast cancer, susceptibility to
Ethnicity/Population group: European caucasoid
Testing laboratory: Fundación Pública Galega Medicina Xenómica (FPGMX), SERGAS, 15706 Santiago de Compostela, Spain
|
|
|
Pathogenic
(Oct 31, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002067402.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the ATM gene demonstrated a 1 base pair deletion in exon 26, c.3802del. This sequence change results in the creation of … (more)
DNA sequence analysis of the ATM gene demonstrated a 1 base pair deletion in exon 26, c.3802del. This sequence change results in the creation of a premature stop codon at amino acid position 1268, p.Val1268*. This sequence change 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. This sequence change has been reported in the gnomAD database with a frequency of 0.0085% in Latino populations (dbSNP rs781357995). The p.Val1268* change has been described in the homozygous and compound heterozygous states in patients with ataxia telangiectasia (PMID: 8755918, 21965147). This pathogenic sequence change has previously been described in the heterozygous state in patients with breast, colon, pancreatic and prostate cancer (PMID: 29478780, 28779002, 21787400, 27433846, 22585167, 29961768). (less)
|
|
|
Pathogenic
(Jul 02, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV000838526.2
First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
|
|
|
Pathogenic
(Feb 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768131.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ataxia-telangiectasia (MIM#208900). (I) 0106 - This gene is associated with autosomal recessive disease. Carriers of ATM pathogenic variants are at increased risk of developing cancer (mainly breast cancer) (GeneReviews). (I) 0115 - Variants in this gene are known to have variable expressivity. Variable age of onset and rate of disease progression have been reported for affected individuals within the same family (PMIDs: 20301790, 27884168). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 11 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple homozygotes and compound heterozygotes individuals with ataxia-telangiectasia, and families with various types of cancer (ClinVar). (SP) 1205 - This variant has been shown to be maternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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|
|
Pathogenic
(Mar 18, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000485724.2
First in ClinVar: Jul 01, 2016 Last updated: Dec 24, 2022 |
|
|
|
Pathogenic
(Jul 13, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Ataxia-telangiectasia syndrome
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002800031.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Dec 09, 2022)
|
criteria provided, single submitter
Method: research
|
Familial cancer of breast
Affected status: no
Allele origin:
germline
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV002762775.2
First in ClinVar: Dec 17, 2022 Last updated: Feb 25, 2023 |
Comment:
PVS1, PS3_MOD, PM3_VSTR
|
|
|
Pathogenic
(Jun 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003807835.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 moderated, PM2 moderated, PM3 moderated
Number of individuals with the variant: 1
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
|
|
|
Pathogenic
(Feb 06, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004243437.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
|
|
|
Pathogenic
(Jan 23, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004931090.1
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
(Apr 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000184776.9
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The c.3802delG pathogenic mutation, located in coding exon 25 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 3802, causing … (more)
The c.3802delG pathogenic mutation, located in coding exon 25 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 3802, causing a translational frameshift with a predicted alternate stop codon (p.V1268*). This alteration has been reported in breast cancer, pancreatic cancer, prostate cancer, colorectal cancer and ataxia-telangiectasia (AT) families to date (McConville CM et al. Am. J. Hum. Genet. 1996 Aug;59:320-30; Goldgar DE et al. Breast Cancer Res. 2011 Jul;13:R73; Roberts NJ et al. Cancer Discov. 2012 Jan;2:41-6; Podralska MJ et al. Mol Genet Genomic Med. 2014 Nov;2:504-11; Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375:443-53; AlDubayan SH et al. Am. J. Hum. Genet. 2018 Mar;102:401-414; Yurgelun MB et al. Genet. Med. 2019 Jan;21:213-223). 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 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002497173.18
First in ClinVar: Apr 08, 2022 Last updated: Oct 20, 2024 |
Comment:
ATM: PVS1, PS4:Moderate, PM2:Supporting
Number of individuals with the variant: 4
|
|
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
|
not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447233.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Breast carcinoma (present)
Sex: female
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|
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Pathogenic
(Nov 03, 2021)
|
criteria provided, single submitter
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: SCV002010820.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
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Pathogenic
(Apr 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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ATM-related cancer predisposition syndrome
Affected status: unknown
Allele origin:
unknown
|
Illumina Laboratory Services, Illumina
Accession: SCV004014740.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
The ATM c.3802del (p.Val1268Ter) nonsense variant, also referred to as c.3801delG, is expected to result in the loss of normal protein function through either protein … (more)
The ATM c.3802del (p.Val1268Ter) nonsense variant, also referred to as c.3801delG, is expected to result in the loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Across a selection of the available literature, this variant has been identified in trans with a likely pathogenic or pathogenic ATM variant in multiple individuals with a diagnosis of ataxia-telangiectasia, including at least one individual whose cells showed evidence of reduced protein expression and kinase activity (PMID: 8755918; 9887333; 25614872; 27664052). In addition, truncating variants in ATM, including the p.Val1268Ter variant, have been associated with an increased risk of breast cancer (OR=3.26; 95% CI 1.82-6.46). This variant has also been reported as a germline variant in individuals with pancreatic, prostate, and other cancers (PMID: 29922827; 28779002; 33436325). This variant is reported in the Genome Aggregation Database in six alleles at a frequency of 0.000088 in the European (non-Finnish) population (version 3.1.2) and has been classified as pathogenic by at least 28 submitters in ClinVar. Based on the collective evidence, the c.3802del (p.Val1268Ter) variant is classified as pathogenic for ATM-related cancer predisposition syndrome. (less)
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Pathogenic
(Jan 20, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004220999.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
This frameshift variant causes the premature termination of ATM protein synthesis. In the literature, it has been reported in individuals with breast or pancreatic cancer … (more)
This frameshift variant causes the premature termination of ATM protein synthesis. In the literature, it has been reported in individuals with breast or pancreatic cancer (PMID: 22585167 (2012), 21787400 (2011), 18384426 (2008), 11606401 (2001)) or in individuals and families with Ataxia-telangiectasia (PMID: 21965147 (2011), 17124347 (2006), 9887333 (1999), 9463314 (1998)). Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Familial pancreatic carcinoma
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001552091.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The ATM p.Val1268X variant was identified in 9 of 8368 proband chromosomes (frequency: 0.001) from Spanish, British, Australian and North American individuals or families with … (more)
The ATM p.Val1268X variant was identified in 9 of 8368 proband chromosomes (frequency: 0.001) from Spanish, British, Australian and North American individuals or families with BRCA1/2 negative breast cancer, metastatic prostate cancer, or pancreatic cancer and was not identified in 2972 control chromosomes from healthy individuals (Brunet 2008 PMID:18384426, Goldgar 2011 PMID:21787400, Grana 2011 PMID:21445571, Pritchard 2016 PMID:27433846, Renwick 2006 PMID:16832357, Roberts 2012 PMID:22585167). The variant was also identified in dbSNP (ID: rs765158119, currently merged with rs587779834) “With Pathogenic allele”, ClinVar (classified pathogenic by GeneDx, Ambry Genetics, Invitae, Counsyl and Color Genomics Inc.), Clinvitae (3x), Cosmic (1x in lymphoid neoplasm), LOVD 3.0 (1x in lymphoid neoplasm), and was not identified in GeneInsight-COGR, MutDB, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.3802delG variant leads to a premature stop codon at position 1268 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the ATM gene are an established mechanism of disease in ATM-associated cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. (less)
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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: SCV001905778.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Pathogenic
(Jun 03, 2024)
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no assertion criteria provided
Method: clinical testing
|
ATM-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004741482.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The ATM c.3802delG variant is predicted to result in premature protein termination (p.Val1268*). This variant has been reported in the homozygous or compound heterozygous states … (more)
The ATM c.3802delG variant is predicted to result in premature protein termination (p.Val1268*). This variant has been reported in the homozygous or compound heterozygous states in several individuals with ataxia telangiectasia (McConville et al. 1996. PubMed ID: 8755918; Stankovic et al. 1998. PubMed ID: 9463314; Sandoval et al. 1999. PubMed ID: 9887333; Podralska et al. 2014. PubMed ID: 25614872), and individuals with breast and pancreatic cancer (Dörk et al. 2001. PubMed ID: 11606401; Roberts et al. 2012. PubMed ID: 22585167). This variant is reported in 0.0085% of alleles in individuals of Latino descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127374/). Nonsense variants in ATM are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
|
Ataxia-telangiectasia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001458192.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Familial cancer of breast
Affected status: yes
Allele origin:
germline
|
Genomics England Pilot Project, Genomics England
Accession: SCV001760262.1
First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021 |
|
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Pathogenic
(Aug 19, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Breast carcinoma
Affected status: yes
Allele origin:
germline
|
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences
Accession: SCV001792254.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Comment:
Invasive Ductal Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Positive HER2 Receptor: Positive
Age: 30-39 years
|
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001929862.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
Familial cancer of breast
Ataxia-telangiectasia syndrome
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:
unknown
|
GenomeConnect - Invitae Patient Insights Network
Accession: SCV004037558.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
Comment:
Variant classified as Pathogenic and reported on 01-28-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report … (more)
Variant classified as Pathogenic and reported on 01-28-2018 by 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:
Breast carcinoma (present) , Family history of cancer (present)
Indication for testing: Diagnostic
Age: 50-59 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: Invitae
Date variant was reported to submitter: 2018-01-28
Testing laboratory interpretation: Pathogenic
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Comment:
Comment:
This variant deletes 1 nucleotide in exon 26 of the ATM gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in the homozygous or compound heterozygous state with an additional pathogenic ATM variant in individuals affected with ataxia-telangiectasia (PMID: 8755918, 9887333, 10864201, 21965147, 25077176, 25614872, 27664052, 34337741). This variant has also been reported in individuals affected with breast cancer (PMID: 16832357, 18384426, 21445571, 21787400), pancreatic cancer (PMID: 22585167), prostate cancer (PMID: 27433846, 33436325), and gastroesophageal junction adenocarcinoma (PMID: 35078243). This variant has been identified in 11/282542 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:
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 in the heterozygous state in individuals with ATM-related cancers (PMID: 11606401, 18384426, 19781682, 22585167, 27433846, 30306255, 29915322, 29961768); 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; Also known as 3801delG; This variant is associated with the following publications: (PMID: 16832357, 25077176, 10330348, 15039971, 29478780, 17124347, 30772474, 32866655, 34637943, 32818697, 30257646, 29922827, 28888541, 34758253, 35047863, 23585524, 19781682, 12497634, 25614872, 25037873, 8755918, 22585167, 26786923, 21787400, 27664052, 10864201, 9463314, 11606401, 18384426, 27433846, 27484032, 21445571, 21965147, 28652578, 28691344, 30306255, 9887333, 12815592, 28779002, 21665257, 26182300, 29915322, 29961768, 30303537, 29625052, 26689913, 26896183, 31589614, 32853339, 33436325, 32338768, 35626031, 33758026, 34445196, 36139606, 35264596, 33804961)
Comment:
Variant summary: ATM c.3802delG (p.Val1268X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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., p.Arg1466X and p.Ser1905fsX25). The variant allele was found at a frequency of 4e-05 in 276948 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (4e-05 vs 0.004), allowing no conclusion about variant significance. c.3802delG has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia as both a homozygous and compound heterozygous allele, indicating the variant is very likely to be associated with disease. At least one publication reports functional data indicating the variant significantly impairs protein expression and kinase activity in patient cells (Carranza_2017). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The c.3802del (p.Val1268*) variant generates a stop codon that is predicted to result in a truncated or absent protein, due to nonsense mediated decay (NMD) (PVS1). It has an allele frequency of 0.0034%, (9/268,016 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.0086%, (3/35,074 alleles) in the the Latino / Admixed American subpopulation (no population frequency criterion met; http://gnomad.broadinstitute.org). It has been reported in at least eighteen ataxia-telangiectasia probands in homozygosis or together with (likely) pathogenic variants, which awards 4 points to this variant as per ClinGen SVI Recommendation for in trans Criterion (PM3_VeryStrong; PMID: 27664052, 10330348, 12815592, 21665257, 21965147, 8755918, 9887333). Moreover, lymphoblastoid cell lines of patients carrying this variant have been reported to have residual or absent ATM protein expression, no detectable ATM p.Ser1981 autophosphorylation, weak transphosphorylation activity of two substrates and intermediate or high radiosensitivity (PS3; PMID: 10864201, 27664052, 25077176). Therefore, this variant meets criteria to be classified as pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PVS1 + PM3_VeryStrong + PS3 (PMID: 33280026).
Comment:
DNA sequence analysis of the ATM gene demonstrated a 1 base pair deletion in exon 26, c.3802del. This sequence change results in the creation of a premature stop codon at amino acid position 1268, p.Val1268*. This sequence change 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. This sequence change has been reported in the gnomAD database with a frequency of 0.0085% in Latino populations (dbSNP rs781357995). The p.Val1268* change has been described in the homozygous and compound heterozygous states in patients with ataxia telangiectasia (PMID: 8755918, 21965147). This pathogenic sequence change has previously been described in the heterozygous state in patients with breast, colon, pancreatic and prostate cancer (PMID: 29478780, 28779002, 21787400, 27433846, 22585167, 29961768).
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ataxia-telangiectasia (MIM#208900). (I) 0106 - This gene is associated with autosomal recessive disease. Carriers of ATM pathogenic variants are at increased risk of developing cancer (mainly breast cancer) (GeneReviews). (I) 0115 - Variants in this gene are known to have variable expressivity. Variable age of onset and rate of disease progression have been reported for affected individuals within the same family (PMIDs: 20301790, 27884168). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 11 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple homozygotes and compound heterozygotes individuals with ataxia-telangiectasia, and families with various types of cancer (ClinVar). (SP) 1205 - This variant has been shown to be maternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
PVS1, PS3_MOD, PM3_VSTR
Comment:
ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 moderated, PM2 moderated, PM3 moderated
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Comment:
The c.3802delG pathogenic mutation, located in coding exon 25 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 3802, causing a translational frameshift with a predicted alternate stop codon (p.V1268*). This alteration has been reported in breast cancer, pancreatic cancer, prostate cancer, colorectal cancer and ataxia-telangiectasia (AT) families to date (McConville CM et al. Am. J. Hum. Genet. 1996 Aug;59:320-30; Goldgar DE et al. Breast Cancer Res. 2011 Jul;13:R73; Roberts NJ et al. Cancer Discov. 2012 Jan;2:41-6; Podralska MJ et al. Mol Genet Genomic Med. 2014 Nov;2:504-11; Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375:443-53; AlDubayan SH et al. Am. J. Hum. Genet. 2018 Mar;102:401-414; Yurgelun MB et al. Genet. Med. 2019 Jan;21:213-223). 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.
Comment:
ATM: PVS1, PS4:Moderate, PM2:Supporting
Comment:
The ATM c.3802del (p.Val1268Ter) nonsense variant, also referred to as c.3801delG, is expected to result in the loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Across a selection of the available literature, this variant has been identified in trans with a likely pathogenic or pathogenic ATM variant in multiple individuals with a diagnosis of ataxia-telangiectasia, including at least one individual whose cells showed evidence of reduced protein expression and kinase activity (PMID: 8755918; 9887333; 25614872; 27664052). In addition, truncating variants in ATM, including the p.Val1268Ter variant, have been associated with an increased risk of breast cancer (OR=3.26; 95% CI 1.82-6.46). This variant has also been reported as a germline variant in individuals with pancreatic, prostate, and other cancers (PMID: 29922827; 28779002; 33436325). This variant is reported in the Genome Aggregation Database in six alleles at a frequency of 0.000088 in the European (non-Finnish) population (version 3.1.2) and has been classified as pathogenic by at least 28 submitters in ClinVar. Based on the collective evidence, the c.3802del (p.Val1268Ter) variant is classified as pathogenic for ATM-related cancer predisposition syndrome.
Comment:
This frameshift variant causes the premature termination of ATM protein synthesis. In the literature, it has been reported in individuals with breast or pancreatic cancer (PMID: 22585167 (2012), 21787400 (2011), 18384426 (2008), 11606401 (2001)) or in individuals and families with Ataxia-telangiectasia (PMID: 21965147 (2011), 17124347 (2006), 9887333 (1999), 9463314 (1998)). Based on the available information, this variant is classified as pathogenic.
Comment:
The ATM p.Val1268X variant was identified in 9 of 8368 proband chromosomes (frequency: 0.001) from Spanish, British, Australian and North American individuals or families with BRCA1/2 negative breast cancer, metastatic prostate cancer, or pancreatic cancer and was not identified in 2972 control chromosomes from healthy individuals (Brunet 2008 PMID:18384426, Goldgar 2011 PMID:21787400, Grana 2011 PMID:21445571, Pritchard 2016 PMID:27433846, Renwick 2006 PMID:16832357, Roberts 2012 PMID:22585167). The variant was also identified in dbSNP (ID: rs765158119, currently merged with rs587779834) “With Pathogenic allele”, ClinVar (classified pathogenic by GeneDx, Ambry Genetics, Invitae, Counsyl and Color Genomics Inc.), Clinvitae (3x), Cosmic (1x in lymphoid neoplasm), LOVD 3.0 (1x in lymphoid neoplasm), and was not identified in GeneInsight-COGR, MutDB, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.3802delG variant leads to a premature stop codon at position 1268 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the ATM gene are an established mechanism of disease in ATM-associated cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Comment:
The ATM c.3802delG variant is predicted to result in premature protein termination (p.Val1268*). This variant has been reported in the homozygous or compound heterozygous states in several individuals with ataxia telangiectasia (McConville et al. 1996. PubMed ID: 8755918; Stankovic et al. 1998. PubMed ID: 9463314; Sandoval et al. 1999. PubMed ID: 9887333; Podralska et al. 2014. PubMed ID: 25614872), and individuals with breast and pancreatic cancer (Dörk et al. 2001. PubMed ID: 11606401; Roberts et al. 2012. PubMed ID: 22585167). This variant is reported in 0.0085% of alleles in individuals of Latino descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127374/). Nonsense variants in ATM are expected to be pathogenic. This variant is interpreted as pathogenic.
Comment:
Invasive Ductal Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Positive HER2 Receptor: Positive
Comment:
Variant classified as Pathogenic and reported on 01-28-2018 by 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:
This sequence change creates a premature translational stop signal (p.Val1268*) 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 (rs765158119, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (A-T), and breast cancer (PMID: 8755918, 9887333, 10330348, 10864201, 11606401, 12815592, 16832357, 18384426, 21787400, 23585524, 25077176, 25614872). It is commonly reported in individuals of British Isles ancestry (PMID: 8755918, 9463314, 9887333, 10330348, 10864201, 11606401, 12815592, 16832357, 18384426, 21787400, 22585167, 23585524, 25077176, 25614872). This variant is also known as c.3801delG. ClinVar contains an entry for this variant (Variation ID: 127374). For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant deletes 1 nucleotide in exon 26 of the ATM gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in the homozygous or compound heterozygous state with an additional pathogenic ATM variant in individuals affected with ataxia-telangiectasia (PMID: 8755918, 9887333, 10864201, 21965147, 25077176, 25614872, 27664052, 34337741). This variant has also been reported in individuals affected with breast cancer (PMID: 16832357, 18384426, 21445571, 21787400), pancreatic cancer (PMID: 22585167), prostate cancer (PMID: 27433846, 33436325), and gastroesophageal junction adenocarcinoma (PMID: 35078243). This variant has been identified in 11/282542 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:
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 in the heterozygous state in individuals with ATM-related cancers (PMID: 11606401, 18384426, 19781682, 22585167, 27433846, 30306255, 29915322, 29961768); 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; Also known as 3801delG; This variant is associated with the following publications: (PMID: 16832357, 25077176, 10330348, 15039971, 29478780, 17124347, 30772474, 32866655, 34637943, 32818697, 30257646, 29922827, 28888541, 34758253, 35047863, 23585524, 19781682, 12497634, 25614872, 25037873, 8755918, 22585167, 26786923, 21787400, 27664052, 10864201, 9463314, 11606401, 18384426, 27433846, 27484032, 21445571, 21965147, 28652578, 28691344, 30306255, 9887333, 12815592, 28779002, 21665257, 26182300, 29915322, 29961768, 30303537, 29625052, 26689913, 26896183, 31589614, 32853339, 33436325, 32338768, 35626031, 33758026, 34445196, 36139606, 35264596, 33804961)
Comment:
Variant summary: ATM c.3802delG (p.Val1268X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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., p.Arg1466X and p.Ser1905fsX25). The variant allele was found at a frequency of 4e-05 in 276948 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (4e-05 vs 0.004), allowing no conclusion about variant significance. c.3802delG has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia as both a homozygous and compound heterozygous allele, indicating the variant is very likely to be associated with disease. At least one publication reports functional data indicating the variant significantly impairs protein expression and kinase activity in patient cells (Carranza_2017). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The c.3802del (p.Val1268*) variant generates a stop codon that is predicted to result in a truncated or absent protein, due to nonsense mediated decay (NMD) (PVS1). It has an allele frequency of 0.0034%, (9/268,016 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.0086%, (3/35,074 alleles) in the the Latino / Admixed American subpopulation (no population frequency criterion met; http://gnomad.broadinstitute.org). It has been reported in at least eighteen ataxia-telangiectasia probands in homozygosis or together with (likely) pathogenic variants, which awards 4 points to this variant as per ClinGen SVI Recommendation for in trans Criterion (PM3_VeryStrong; PMID: 27664052, 10330348, 12815592, 21665257, 21965147, 8755918, 9887333). Moreover, lymphoblastoid cell lines of patients carrying this variant have been reported to have residual or absent ATM protein expression, no detectable ATM p.Ser1981 autophosphorylation, weak transphosphorylation activity of two substrates and intermediate or high radiosensitivity (PS3; PMID: 10864201, 27664052, 25077176). Therefore, this variant meets criteria to be classified as pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PVS1 + PM3_VeryStrong + PS3 (PMID: 33280026).
Comment:
DNA sequence analysis of the ATM gene demonstrated a 1 base pair deletion in exon 26, c.3802del. This sequence change results in the creation of a premature stop codon at amino acid position 1268, p.Val1268*. This sequence change 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. This sequence change has been reported in the gnomAD database with a frequency of 0.0085% in Latino populations (dbSNP rs781357995). The p.Val1268* change has been described in the homozygous and compound heterozygous states in patients with ataxia telangiectasia (PMID: 8755918, 21965147). This pathogenic sequence change has previously been described in the heterozygous state in patients with breast, colon, pancreatic and prostate cancer (PMID: 29478780, 28779002, 21787400, 27433846, 22585167, 29961768).
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ataxia-telangiectasia (MIM#208900). (I) 0106 - This gene is associated with autosomal recessive disease. Carriers of ATM pathogenic variants are at increased risk of developing cancer (mainly breast cancer) (GeneReviews). (I) 0115 - Variants in this gene are known to have variable expressivity. Variable age of onset and rate of disease progression have been reported for affected individuals within the same family (PMIDs: 20301790, 27884168). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 11 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple homozygotes and compound heterozygotes individuals with ataxia-telangiectasia, and families with various types of cancer (ClinVar). (SP) 1205 - This variant has been shown to be maternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
PVS1, PS3_MOD, PM3_VSTR
Comment:
ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 moderated, PM2 moderated, PM3 moderated
Comment:
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Comment:
The c.3802delG pathogenic mutation, located in coding exon 25 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 3802, causing a translational frameshift with a predicted alternate stop codon (p.V1268*). This alteration has been reported in breast cancer, pancreatic cancer, prostate cancer, colorectal cancer and ataxia-telangiectasia (AT) families to date (McConville CM et al. Am. J. Hum. Genet. 1996 Aug;59:320-30; Goldgar DE et al. Breast Cancer Res. 2011 Jul;13:R73; Roberts NJ et al. Cancer Discov. 2012 Jan;2:41-6; Podralska MJ et al. Mol Genet Genomic Med. 2014 Nov;2:504-11; Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375:443-53; AlDubayan SH et al. Am. J. Hum. Genet. 2018 Mar;102:401-414; Yurgelun MB et al. Genet. Med. 2019 Jan;21:213-223). 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.
Comment:
ATM: PVS1, PS4:Moderate, PM2:Supporting
Comment:
The ATM c.3802del (p.Val1268Ter) nonsense variant, also referred to as c.3801delG, is expected to result in the loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Across a selection of the available literature, this variant has been identified in trans with a likely pathogenic or pathogenic ATM variant in multiple individuals with a diagnosis of ataxia-telangiectasia, including at least one individual whose cells showed evidence of reduced protein expression and kinase activity (PMID: 8755918; 9887333; 25614872; 27664052). In addition, truncating variants in ATM, including the p.Val1268Ter variant, have been associated with an increased risk of breast cancer (OR=3.26; 95% CI 1.82-6.46). This variant has also been reported as a germline variant in individuals with pancreatic, prostate, and other cancers (PMID: 29922827; 28779002; 33436325). This variant is reported in the Genome Aggregation Database in six alleles at a frequency of 0.000088 in the European (non-Finnish) population (version 3.1.2) and has been classified as pathogenic by at least 28 submitters in ClinVar. Based on the collective evidence, the c.3802del (p.Val1268Ter) variant is classified as pathogenic for ATM-related cancer predisposition syndrome.
Comment:
This frameshift variant causes the premature termination of ATM protein synthesis. In the literature, it has been reported in individuals with breast or pancreatic cancer (PMID: 22585167 (2012), 21787400 (2011), 18384426 (2008), 11606401 (2001)) or in individuals and families with Ataxia-telangiectasia (PMID: 21965147 (2011), 17124347 (2006), 9887333 (1999), 9463314 (1998)). Based on the available information, this variant is classified as pathogenic.
Comment:
The ATM p.Val1268X variant was identified in 9 of 8368 proband chromosomes (frequency: 0.001) from Spanish, British, Australian and North American individuals or families with BRCA1/2 negative breast cancer, metastatic prostate cancer, or pancreatic cancer and was not identified in 2972 control chromosomes from healthy individuals (Brunet 2008 PMID:18384426, Goldgar 2011 PMID:21787400, Grana 2011 PMID:21445571, Pritchard 2016 PMID:27433846, Renwick 2006 PMID:16832357, Roberts 2012 PMID:22585167). The variant was also identified in dbSNP (ID: rs765158119, currently merged with rs587779834) “With Pathogenic allele”, ClinVar (classified pathogenic by GeneDx, Ambry Genetics, Invitae, Counsyl and Color Genomics Inc.), Clinvitae (3x), Cosmic (1x in lymphoid neoplasm), LOVD 3.0 (1x in lymphoid neoplasm), and was not identified in GeneInsight-COGR, MutDB, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.3802delG variant leads to a premature stop codon at position 1268 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the ATM gene are an established mechanism of disease in ATM-associated cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Comment:
The ATM c.3802delG variant is predicted to result in premature protein termination (p.Val1268*). This variant has been reported in the homozygous or compound heterozygous states in several individuals with ataxia telangiectasia (McConville et al. 1996. PubMed ID: 8755918; Stankovic et al. 1998. PubMed ID: 9463314; Sandoval et al. 1999. PubMed ID: 9887333; Podralska et al. 2014. PubMed ID: 25614872), and individuals with breast and pancreatic cancer (Dörk et al. 2001. PubMed ID: 11606401; Roberts et al. 2012. PubMed ID: 22585167). This variant is reported in 0.0085% of alleles in individuals of Latino descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127374/). Nonsense variants in ATM are expected to be pathogenic. This variant is interpreted as pathogenic.
Comment:
Invasive Ductal Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Positive HER2 Receptor: Positive
Comment:
Variant classified as Pathogenic and reported on 01-28-2018 by 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Ataxia-Telangiectasia. | Adam MP | - | 2023 | PMID: 20301790 |
| 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 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 |
| Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study. | Karlsson Q | European urology oncology | 2021 | PMID: 33436325 |
| A Collaborative Effort to Define Classification Criteria for ATM Variants in Hereditary Cancer Patients. | Feliubadaló L | Clinical chemistry | 2021 | PMID: 33280026 |
| Germline Sequencing DNA Repair Genes in 5545 Men With Aggressive and Nonaggressive Prostate Cancer. | Darst BF | Journal of the National Cancer Institute | 2021 | PMID: 32853339 |
| Rare germline genetic variants and risk of aggressive prostate cancer. | Nguyen-Dumont T | International journal of cancer | 2020 | PMID: 32338768 |
| ATM mutation spectrum in Russian children with ataxia-telangiectasia. | Suspitsin E | European journal of medical genetics | 2020 | PMID: 30772474 |
| Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes. | Capalbo A | PLoS genetics | 2019 | PMID: 31589614 |
| Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing. | Girard E | International journal of cancer | 2019 | PMID: 30303537 |
| Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer. | Yurgelun MB | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 29961768 |
| Multigene panel testing beyond BRCA1/2 in breast/ovarian cancer Spanish families and clinical actionability of findings. | Bonache S | Journal of cancer research and clinical oncology | 2018 | PMID: 30306255 |
| Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer. | Hu C | JAMA | 2018 | PMID: 29922827 |
| Rare germline variants in DNA repair genes and the angiogenesis pathway predispose prostate cancer patients to develop metastatic disease. | Mijuskovic M | British journal of cancer | 2018 | PMID: 29915322 |
| Pathogenic Germline Variants in 10,389 Adult Cancers. | Huang KL | Cell | 2018 | PMID: 29625052 |
| Inherited DNA-Repair Defects in Colorectal Cancer. | AlDubayan SH | American journal of human genetics | 2018 | PMID: 29478780 |
| Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks. | Decker B | Journal of medical genetics | 2017 | PMID: 28779002 |
| Rare germline variants in ATM are associated with chronic lymphocytic leukemia. | Tiao G | Leukemia | 2017 | PMID: 28652578 |
| Molecular and Functional Characterization of a Cohort of Spanish Patients with Ataxia-Telangiectasia. | Carranza D | Neuromolecular medicine | 2017 | PMID: 27664052 |
| Ataxia telangiectasia: a review. | Rothblum-Oviatt C | Orphanet journal of rare diseases | 2016 | PMID: 27884168 |
| Rapid molecular diagnostics of severe primary immunodeficiency determined by using targeted next-generation sequencing. | Yu H | The Journal of allergy and clinical immunology | 2016 | PMID: 27484032 |
| Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. | Pritchard CC | The New England journal of medicine | 2016 | PMID: 27433846 |
| Longitudinal analysis of the neurological features of ataxia-telangiectasia. | Jackson TJ | Developmental medicine and child neurology | 2016 | PMID: 26896183 |
| Patterns and functional implications of rare germline variants across 12 cancer types. | Lu C | Nature communications | 2015 | PMID: 26689913 |
| Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond. | Hansford S | JAMA oncology | 2015 | PMID: 26182300 |
| Ten new ATM alterations in Polish patients with ataxia-telangiectasia. | Podralska MJ | Molecular genetics & genomic medicine | 2014 | PMID: 25614872 |
| A-TWinnipeg: Pathogenesis of rare ATM missense mutation c.6200C>A with decreased protein expression and downstream signaling, early-onset dystonia, cancer, and life-threatening radiotoxicity. | Nakamura K | Molecular genetics & genomic medicine | 2014 | PMID: 25077176 |
| Twelve novel Atm mutations identified in Chinese ataxia telangiectasia patients. | Huang Y | Neuromolecular medicine | 2013 | PMID: 23807571 |
| ATM mutations uniformly lead to ATM dysfunction in chronic lymphocytic leukemia: application of functional test using doxorubicin. | Navrkalova V | Haematologica | 2013 | PMID: 23585524 |
| ATM mutations in patients with hereditary pancreatic cancer. | Roberts NJ | Cancer discovery | 2012 | PMID: 22585167 |
| New mutations in the ATM gene and clinical data of 25 AT patients. | Demuth I | Neurogenetics | 2011 | PMID: 21965147 |
| Rare variants in the ATM gene and risk of breast cancer. | Goldgar DE | Breast cancer research : BCR | 2011 | PMID: 21787400 |
| Morbidity and mortality from ataxia-telangiectasia are associated with ATM genotype. | Micol R | The Journal of allergy and clinical immunology | 2011 | PMID: 21665257 |
| Germline ATM mutational analysis in BRCA1/BRCA2 negative hereditary breast cancer families by MALDI-TOF mass spectrometry. | Graña B | Breast cancer research and treatment | 2011 | PMID: 21445571 |
| Founder effects for ATM gene mutations in Italian Ataxia Telangiectasia families. | Chessa L | Annals of human genetics | 2009 | PMID: 19691550 |
| ATM germline mutations in Spanish early-onset breast cancer patients negative for BRCA1/BRCA2 mutations. | Brunet J | Clinical genetics | 2008 | PMID: 18384426 |
| DHPLC screening of ATM gene in Italian patients affected by ataxia-telangiectasia: fourteen novel ATM mutations. | Magliozzi M | Disease markers | 2006 | PMID: 17124347 |
| ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. | Renwick A | Nature genetics | 2006 | PMID: 16832357 |
| Five haplotypes account for fifty-five percent of ATM mutations in Brazilian patients with ataxia telangiectasia: seven new mutations. | Coutinho G | American journal of medical genetics. Part A | 2004 | PMID: 15039971 |
| Independent mutational events are rare in the ATM gene: haplotype prescreening enhances mutation detection rate. | Mitui M | Human mutation | 2003 | PMID: 12815592 |
| Spectrum of ATM gene mutations in a hospital-based series of unselected breast cancer patients. | Dörk T | Cancer research | 2001 | PMID: 11606401 |
| ATM protein and p53-serine 15 phosphorylation in ataxia-telangiectasia (AT) patients and at heterozygotes. | Delia D | British journal of cancer | 2000 | PMID: 10864201 |
| 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 |
| ATM mutations and phenotypes in ataxia-telangiectasia families in the British Isles: expression of mutant ATM and the risk of leukemia, lymphoma, and breast cancer. | Stankovic T | American journal of human genetics | 1998 | PMID: 9463314 |
| Mutations associated with variant phenotypes in ataxia-telangiectasia. | McConville CM | American journal of human genetics | 1996 | PMID: 8755918 |
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Text-mined citations for rs587779834 ...
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Record last updated Nov 10, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.