NM_000051.4(ATM):c.7997C>T (p.Thr2666Ile) AND Ataxia-telangiectasia syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 1, 2021
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:: RCV002005123.11

Allele description [Variation Report for NM_000051.4(ATM):c.7997C>T (p.Thr2666Ile)]

NM_000051.4(ATM):c.7997C>T (p.Thr2666Ile)

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.7997C>T (p.Thr2666Ile)

HGVS:

NC_000011.10:g.108333955C>T
NG_009830.1:g.116124C>T
NG_054724.1:g.140878G>A
NM_000051.4:c.7997C>TMANE SELECT
NM_001330368.2:c.641-24884G>A
NM_001351110.2:c.*38+1265G>A
NM_001351834.2:c.7997C>T
NP_000042.3:p.Thr2666Ile
NP_000042.3:p.Thr2666Ile
NP_001338763.1:p.Thr2666Ile
LRG_135t1:c.7997C>T
LRG_135:g.116124C>T
LRG_135p1:p.Thr2666Ile
NC_000011.9:g.108204682C>T
NM_000051.3:c.7997C>T

Protein change:

T2666I

Links:

dbSNP: rs730881384

NCBI 1000 Genomes Browser:

rs730881384

Molecular consequence:

NM_001330368.2:c.641-24884G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.*38+1265G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000051.4:c.7997C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.7997C>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002259517	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 1, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26633542, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002259517

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 1, 2021)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

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

Citations

PubMed

Clinical application of whole-exome sequencing across clinical indications.

Retterer K, Juusola J, Cho MT, Vitazka P, Millan F, Gibellini F, Vertino-Bell A, Smaoui N, Neidich J, Monaghan KG, McKnight D, Bai R, Suchy S, Friedman B, Tahiliani J, Pineda-Alvarez D, Richard G, Brandt T, Haverfield E, Chung WK, Bale S.

Genet Med. 2016 Jul;18(7):696-704. doi: 10.1038/gim.2015.148. Epub 2015 Dec 3.

PubMed [citation]

PMID:: 26633542

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV002259517.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Thr2666 amino acid residue in ATM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26633542; Invitae; external communication). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATM protein function. 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 replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 2666 of the ATM protein (p.Thr2666Ile).

#	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: May 1, 2024

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