NM_000051.4(ATM):c.7879T>C (p.Tyr2627His) AND Ataxia-telangiectasia syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 11, 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:: RCV001862671.14

Allele description [Variation Report for NM_000051.4(ATM):c.7879T>C (p.Tyr2627His)]

NM_000051.4(ATM):c.7879T>C (p.Tyr2627His)

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.7879T>C (p.Tyr2627His)

HGVS:

NC_000011.10:g.108332852T>C
NG_009830.1:g.115021T>C
NG_054724.1:g.141981A>G
NM_000051.4:c.7879T>CMANE SELECT
NM_001330368.2:c.641-23781A>G
NM_001351110.2:c.*38+2368A>G
NM_001351834.2:c.7879T>C
NP_000042.3:p.Tyr2627His
NP_000042.3:p.Tyr2627His
NP_001338763.1:p.Tyr2627His
LRG_135t1:c.7879T>C
LRG_135:g.115021T>C
LRG_135p1:p.Tyr2627His
NC_000011.9:g.108203579T>C
NC_000011.9:g.108203579T>C
NM_000051.3:c.7879T>C

Protein change:

Y2627H

Links:

dbSNP: rs2086422796

NCBI 1000 Genomes Browser:

rs2086422796

Molecular consequence:

NM_001330368.2:c.641-23781A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.*38+2368A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000051.4:c.7879T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.7879T>C - 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
SCV002239460	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 11, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22071889, 27664052, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002239460

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 11, 2021)

germline

clinical testing

PubMed (3)
[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

Underexpression and abnormal localization of ATM products in ataxia telangiectasia patients bearing ATM missense mutations.

Jacquemin V, Rieunier G, Jacob S, Bellanger D, d'Enghien CD, Laugé A, Stoppa-Lyonnet D, Stern MH.

Eur J Hum Genet. 2012 Mar;20(3):305-12. doi: 10.1038/ejhg.2011.196. Epub 2011 Nov 9.

PubMed [citation]

PMID:: 22071889
PMCID:: PMC3283185

Molecular and Functional Characterization of a Cohort of Spanish Patients with Ataxia-Telangiectasia.

Carranza D, Vega AK, Torres-Rusillo S, Montero E, Martinez LJ, Santamaría M, Santos JL, Molina IJ.

Neuromolecular Med. 2017 Mar;19(1):161-174. doi: 10.1007/s12017-016-8440-8. Epub 2016 Sep 23.

PubMed [citation]

PMID:: 27664052

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002239460.3

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

Description

For these reasons, this variant has been classified as Pathogenic. 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. Experimental studies have shown that this variant affects ATM protein function (PMID: 27664052). This variant has been observed in individuals with ataxia-telangiectasia (PMID: 22071889, 27664052). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 870645). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with histidine at codon 2627 of the ATM protein (p.Tyr2627His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine.

#	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 10, 2024

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