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NM_000051.4(ATM):c.6095G>T (p.Arg2032Ile) AND Ataxia-telangiectasia syndrome

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Jul 1, 2019
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV001223230.16

Allele description [Variation Report for NM_000051.4(ATM):c.6095G>T (p.Arg2032Ile)]

NM_000051.4(ATM):c.6095G>T (p.Arg2032Ile)

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>T (p.Arg2032Ile)
HGVS:
  • NC_000011.10:g.108315911G>T
  • NG_009830.1:g.98080G>T
  • NG_054724.1:g.158922C>A
  • NM_000051.4:c.6095G>TMANE SELECT
  • NM_001330368.2:c.641-6840C>A
  • NM_001351110.2:c.*39-6840C>A
  • NM_001351834.2:c.6095G>T
  • NP_000042.3:p.Arg2032Ile
  • NP_000042.3:p.Arg2032Ile
  • NP_001338763.1:p.Arg2032Ile
  • LRG_135t1:c.6095G>T
  • LRG_135:g.98080G>T
  • LRG_135p1:p.Arg2032Ile
  • NC_000011.9:g.108186638G>T
  • NM_000051.3:c.6095G>T
Protein change:
R2032I
Links:
dbSNP: rs139770721
NCBI 1000 Genomes Browser:
rs139770721
Molecular consequence:
  • NM_001330368.2:c.641-6840C>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001351110.2:c.*39-6840C>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000051.4:c.6095G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001351834.2:c.6095G>T - 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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001395369Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Jul 1, 2019) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Characterization of ATM gene mutations in 66 ataxia telangiectasia families.

Sandoval N, Platzer M, Rosenthal A, Dörk T, Bendix R, Skawran B, Stuhrmann M, Wegner RD, Sperling K, Banin S, Shiloh Y, Baumer A, Bernthaler U, Sennefelder H, Brohm M, Weber BH, Schindler D.

Hum Mol Genet. 1999 Jan;8(1):69-79.

PubMed [citation]
PMID:
9887333

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 (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001395369.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the c.6095G nucleotide in the ATM gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 9887333). This suggests that this nucleotide is clinically-significant, and that variants that disrupt this position are likely to be disease-causing. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with ATM-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with isoleucine at codon 2032 of the ATM protein (p.Arg2032Ile). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and isoleucine. This variant also falls at the last nucleotide of exon 41 of the ATM coding sequence, which is part of the consensus splice site for this exon.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 3, 2024