NM_000051.4(ATM):c.6095G>A (p.Arg2032Lys) AND Ataxia-telangiectasia syndrome

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Dec 25, 2023
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:: RCV000167946.28

Allele description [Variation Report for NM_000051.4(ATM):c.6095G>A (p.Arg2032Lys)]

NM_000051.4(ATM):c.6095G>A (p.Arg2032Lys)

Genes:

ATM:ATM serine/threonine kinase [Gene - OMIM - HGNC]
C11orf65:chromosome 11 open reading frame 65 [Gene - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q22.3

Genomic location:

Preferred name:

NM_000051.4(ATM):c.6095G>A (p.Arg2032Lys)

Other names:

p.R2032K:AGA>AAA

HGVS:

NC_000011.10:g.108315911G>A
NG_009830.1:g.98080G>A
NG_054724.1:g.158922C>T
NM_000051.4:c.6095G>AMANE SELECT
NM_001330368.2:c.641-6840C>T
NM_001351110.2:c.*39-6840C>T
NM_001351834.2:c.6095G>A
NP_000042.3:p.Arg2032Lys
NP_000042.3:p.Arg2032Lys
NP_001338763.1:p.Arg2032Lys
LRG_135t1:c.6095G>A
LRG_135:g.98080G>A
LRG_135p1:p.Arg2032Lys
NC_000011.9:g.108186638G>A
NM_000051.3:c.6095G>A
p.R2032K

Protein change:

R2032K

Links:

dbSNP: rs139770721

NCBI 1000 Genomes Browser:

rs139770721

Molecular consequence:

NM_001330368.2:c.641-6840C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.*39-6840C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000051.4:c.6095G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.6095G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000218594	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 25, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 10330348, 10980530, 16266405, 22585167, 25614872, 26506520, 27159176, 17576681, 9536098, 9887333, 28492532
SCV000220988	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Dec 23, 2014)	unknown	literature only	PubMed (5) [See all records that cite these PMIDs] 16266405, 15390180, 20153123, 9887333, 10980530 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV000694316	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 7, 2015)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 10980530, 12810666, 26506520, 10330348, 9887333, 22585167, 25614872, 16266405, 10817650 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV002020687	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 31, 2019)	germline	clinical testing	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	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Allogeneic-matched sibling stem cell transplantation in a 13-year-old boy with ataxia telangiectasia and EBV-positive non-Hodgkin lymphoma.

Beier R, Sykora KW, Woessmann W, Maecker-Kolhoff B, Sauer M, Kreipe HH, Dörk-Bousset T, Kratz C, Lauten M.

Bone Marrow Transplant. 2016 Sep;51(9):1271-4. doi: 10.1038/bmt.2016.93. Epub 2016 May 9. No abstract available.

PubMed [citation]

PMID:: 27159176

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]

PMID:: 17576681
PMCID:: PMC1934990

See all PubMed Citations (16)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000218594.13

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 2032 of the ATM protein (p.Arg2032Lys). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs139770721, gnomAD 0.006%). This missense change has been observed in individuals with ataxia-telangiectasia, pancreatic cancer, or gastric cancer (PMID: 9887333, 10330348, 10980530, 16266405, 22585167, 25614872, 26506520, 27159176). ClinVar contains an entry for this variant (Variation ID: 181974). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 41 (also referred to as exon 43) and introduces a premature termination codon (PMID: 9887333; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. 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 Counsyl, SCV000220988.2

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000694316.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

#	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, SCV002020687.3

#	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

Last Updated: Nov 3, 2024

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