NM_000051.4(ATM):c.5712dup (p.Ser1905fs) AND Ataxia-telangiectasia syndrome

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Jan 18, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000169006.22

Allele description [Variation Report for NM_000051.4(ATM):c.5712dup (p.Ser1905fs)]

NM_000051.4(ATM):c.5712dup (p.Ser1905fs)

Gene:

ATM:ATM serine/threonine kinase [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

11q22.3

Genomic location:

Preferred name:

NM_000051.4(ATM):c.5712dup (p.Ser1905fs)

HGVS:

NC_000011.10:g.108307934dup
NG_009830.1:g.90103dup
NG_054724.1:g.166904dup
NM_000051.4:c.5712dupMANE SELECT
NM_001351834.2:c.5712dup
NP_000042.3:p.Ser1905fs
NP_000042.3:p.Ser1905fs
NP_001338763.1:p.Ser1905fs
LRG_135t1:c.5712dup
LRG_135:g.90103dup
LRG_135p1:p.Ser1905fs
NC_000011.9:g.108178655_108178656insA
NC_000011.9:g.108178661dup
NM_000051.3:c.5712dup
NM_000051.3:c.5712dupA
NM_000051.4:c.5712dupAMANE SELECT
p.S1905Ifs*25
p.S1905IfsX25

Protein change:

S1905fs

Links:

dbSNP: rs587781730

NCBI 1000 Genomes Browser:

rs587781730

Molecular consequence:

NM_000051.4:c.5712dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001351834.2:c.5712dup - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Ataxia-telangiectasia syndrome (AT)
Synonyms:: Louis-Bar syndrome; Cerebello-oculocutaneous telangiectasia; Immunodeficiency with ataxia telangiectasia; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008840; MedGen: C0004135; Orphanet: 100; OMIM: 208900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000220146	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Mar 7, 2014)	unknown	literature only	PubMed (5) [See all records that cite these PMIDs] 10873394, 16266405, 7792600, 10817650, 8845835 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV000547052	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 18, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 23807571, 25614872, 8845835, 10817650, 10873394, 16266405, 26681312, 28492532
SCV000838556	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Pathogenic (Jul 2, 2018)	unknown	clinical testing	Citation Link,
SCV000916572	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 9, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 8845835, 26681312, 25186627 Citation Link,
SCV002021242	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 6, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002077226	Natera, Inc.	no assertion criteria provided	Pathogenic (Jan 27, 2021)	germline	clinical testing
SCV003936078	Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences	no assertion criteria provided	Pathogenic	inherited	research	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	inherited	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A single ataxia telangiectasia gene with a product similar to PI-3 kinase.

Savitsky K, Bar-Shira A, Gilad S, Rotman G, Ziv Y, Vanagaite L, Tagle DA, Smith S, Uziel T, Sfez S, Ashkenazi M, Pecker I, Frydman M, Harnik R, Patanjali SR, Simmons A, Clines GA, Sartiel A, Gatti RA, Chessa L, Sanal O, Lavin MF, et al.

Science. 1995 Jun 23;268(5218):1749-53.

PubMed [citation]

PMID:: 7792600

Twelve novel Atm mutations identified in Chinese ataxia telangiectasia patients.

Huang Y, Yang L, Wang J, Yang F, Xiao Y, Xia R, Yuan X, Yan M.

Neuromolecular Med. 2013 Sep;15(3):536-40. doi: 10.1007/s12017-013-8240-3. Epub 2013 Jun 27. Erratum in: Neuromolecular Med. 2014 Mar;16(1):216.

PubMed [citation]

PMID:: 23807571
PMCID:: PMC3732755

See all PubMed Citations (11)

Details of each submission

From Counsyl, SCV000220146.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (5)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV000547052.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change creates a premature translational stop signal (p.Ser1905Ilefs*25) 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 (rs587781730, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with pancreatic cancer and ataxia-telangiectasia (PMID: 8845835, 10817650, 10873394, 16266405, 26681312). ClinVar contains an entry for this variant (Variation ID: 141416). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mendelics, SCV000838556.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000916572.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: ATM c.5712dupA (p.Ser1905IlefsX25) 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. The variant allele was found at a frequency of 8.1e-06 in 245942 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (8.1e-06 vs 4.00e-03), allowing no conclusion about variant significance. The variant, c.5712dupA, has been reported in the literature in individuals affected with Ataxia-Telangiectasia, breast, and pancreatic cancer (Susswein_2016, Tung_2015, Gilad_1996). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002021242.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV002077226.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, SCV003936078.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		not provided	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 23, 2024

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