VCV000419910.17 - ClinVar

NM_000051.4(ATM):c.5894_5900dup (p.Met1967fs)

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.

(5)

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

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000051.4(ATM):c.5894_5900dup (p.Met1967fs)

Variation ID: 419910 Accession: VCV000419910.17

Type and length

Duplication, 7 bp

Location

Cytogenetic: 11q22.3 11: 108310290-108310291 (GRCh38) [ NCBI UCSC ] 11: 108181017-108181018 (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	Apr 27, 2017	May 1, 2024	Jan 26, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000051.4:c.5894_5900dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000042.3:p.Met1967fs	frameshift
NM_000051.3:c.5894_5900dupAAAGTAT		frameshift
NM_001330368.2:c.641-1226_641-1220dup		intron variant
NM_001351110.2:c.39-1226_39-1220dup		intron variant
NM_001351834.2:c.5894_5900dup	NP_001338763.1:p.Met1967fs	frameshift
NC_000011.10:g.108310291_108310297dup
NC_000011.9:g.108181018_108181024dup
NG_009830.1:g.92460_92466dup
NG_054724.1:g.164536_164542dup
LRG_135:g.92460_92466dup
LRG_135t1:c.5894_5900dup	LRG_135p1:p.Met1967Ilefs

... more HGVS ... less HGVS

Protein change

M1967fs

Other names

Canonical SPDI

NC_000011.10:108310290:AAAGTAT:AAAGTATAAAGTAT

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.

Links

ClinGen: CA16619205 dbSNP: rs1555110517 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	10842	17443
C11orf65	-	-	-	GRCh38 GRCh37	3	6583

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.
not provided	Likely pathogenic (1)	criteria provided, single submitter	Oct 8, 2015	RCV000479472.10
Hereditary cancer-predisposing syndrome	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Apr 20, 2020	RCV000583009.16
Ataxia-telangiectasia syndrome	Pathogenic (1)	criteria provided, single submitter	Apr 28, 2023	RCV001037468.15
Familial cancer of breast	Pathogenic (1)	criteria provided, single submitter	Jan 26, 2024	RCV004023129.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Oct 08, 2015)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000568109.4 First in ClinVar: Apr 27, 2017 Last updated: Apr 27, 2017	Comment: This duplication of 7 nucleotides in ATM is denoted c.5894_5900dupAAAGTAT at the cDNA level and p.Met1967IlefsX5 (M1967IfsX5) at the protein level. The normal sequence, with … (more) This duplication of 7 nucleotides in ATM is denoted c.5894_5900dupAAAGTAT at the cDNA level and p.Met1967IlefsX5 (M1967IfsX5) at the protein level. The normal sequence, with the bases that are duplicated in braces, is AAGA[AAAGTAT]GGAT. The duplication causes a frameshift, which changes a Methionine to an Isoleucine at codon 1967, and creates a premature stop codon at position 5 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Based on the currently available information, we consider this duplication to be a likely pathogenic variant. (less)
Pathogenic (Apr 20, 2020)	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: SCV000687649.3 First in ClinVar: Feb 19, 2018 Last updated: Jan 15, 2022	Comment: This variant inserts 7 nucleotides in exon 39 of the ATM gene, creating a frameshift and premature translation stop signal. This variant is expected to … (more) This variant inserts 7 nucleotides in exon 39 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. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. (less)
Pathogenic (Apr 28, 2023)	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: SCV001200883.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024	Publications: PubMed (2) PubMed: 23807571‚ 25614872 Comment: For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 419910). This variant has not been … (more) For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 419910). This variant has not been reported in the literature in individuals affected with ATM-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Met1967Ilefs*5) 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). (less)
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: SCV004933711.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Comment: This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Pathogenic (Sep 16, 2019)	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: SCV001186699.4 First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024	Comment: The c.5894_5900dupAAAGTAT pathogenic mutation, located in coding exon 38 of the ATM gene, results from a duplication of AAAGTAT at nucleotide position 5894, causing a … (more) The c.5894_5900dupAAAGTAT pathogenic mutation, located in coding exon 38 of the ATM gene, results from a duplication of AAAGTAT at nucleotide position 5894, causing a translational frameshift with a predicted alternate stop codon (p.M1967Ifs*5). 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)

Comment:

This duplication of 7 nucleotides in ATM is denoted c.5894_5900dupAAAGTAT at the cDNA level and p.Met1967IlefsX5 (M1967IfsX5) at the protein level. The normal sequence, with the bases that are duplicated in braces, is AAGA[AAAGTAT]GGAT. The duplication causes a frameshift, which changes a Methionine to an Isoleucine at codon 1967, and creates a premature stop codon at position 5 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Based on the currently available information, we consider this duplication to be a likely pathogenic variant.

Comment:

This variant inserts 7 nucleotides in exon 39 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. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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:

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 419910). This variant has not been reported in the literature in individuals affected with ATM-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Met1967Ilefs*5) 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).

Comment:

The c.5894_5900dupAAAGTAT pathogenic mutation, located in coding exon 38 of the ATM gene, results from a duplication of AAAGTAT at nucleotide position 5894, causing a translational frameshift with a predicted alternate stop codon (p.M1967Ifs*5). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

Germline Functional Evidence

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

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
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

Text-mined citations for rs1555110517 ...

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 19, 2024

ClinVar Genomic variation as it relates to human health

NM_000051.4(ATM):c.5894_5900dup (p.Met1967fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1555110517 ...