NM_000051.3(ATM):c.7475T>G (p.Leu2492Arg) AND Ataxia-telangiectasia syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Conflicting classifications of pathogenicity (5 submissions)
Last evaluated:: Jan 9, 2020
Review status:: criteria provided, conflicting classifications

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:: RCV000195623.11

Allele description

NM_000051.3(ATM):c.7475T>G (p.Leu2492Arg)

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_000051.3(ATM):c.7475T>G (p.Leu2492Arg)

Other names:

p.L2492R:CTT>CGT

HGVS:

NC_000011.10:g.108330381T>G
NG_009830.1:g.112550T>G
NG_054724.1:g.144452A>C
NM_000051.3:c.7475T>G
NM_001330368.2:c.641-21310A>C
NM_001351110.2:c.38+4839A>C
NM_001351834.2:c.7475T>G
NP_000042.3:p.Leu2492Arg
NP_001338763.1:p.Leu2492Arg
LRG_135t1:c.7475T>G
LRG_135:g.112550T>G
LRG_135p1:p.Leu2492Arg
NC_000011.9:g.108201108T>G
Q13315:p.Leu2492Arg
p.L2492R

Protein change:

L2492R

Links:

UniProtKB: Q13315#VAR_041579; dbSNP: rs56399857

NCBI 1000 Genomes Browser:

rs56399857

Molecular consequence:

NM_001330368.2:c.641-21310A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.38+4839A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000051.3:c.7475T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.7475T>G - 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
SCV000254145	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Jan 9, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000732995	Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Uncertain significance	germline	clinical testing
SCV000745132	DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center - VKGL Data-share Consensus	criteria provided, single submitter (ACGS Guidelines, 2013)	Uncertain significance (May 31, 2017)	germline	clinical testing	Citation Link,
SCV000800168	Counsyl	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018))	Uncertain significance (May 24, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001160197	ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Uncertain significance (Jan 25, 2019)	germline	clinical testing	Citation Link

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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	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

GESPA: classifying nsSNPs to predict disease association.

Khurana JK, Reeder JE, Shrimpton AE, Thakar J.

BMC Bioinformatics. 2015 Jul 25;16:228. doi: 10.1186/s12859-015-0673-2.

PubMed [citation]

PMID:: 26206375
PMCID:: PMC4513380

Details of each submission

From Invitae, SCV000254145.8

#	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 Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen - VKGL Data-share Consensus, SCV000732995.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center - VKGL Data-share Consensus, SCV000745132.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV000800168.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories, SCV001160197.1

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

Description

The ATM c.7475T>G; p.Leu2492Arg variant (rs56399857) is reported in the literature in individuals with colorectal cancer (Yurgelun 2017), chronic lymphocytic leukemia (Tiao 2017), and glioblastoma multiforme (Lu 2015). This variant is reported with uncertain significance by multiple laboratories in ClinVar (Variation ID: 127446). It is found in the general population with an overall allele frequency of 0.01% (32/282684 alleles) in the Genome Aggregation Database. The leucine at codon 2492 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Lu C et al. Patterns and functional implications of rare germline variants across 12 cancer types. Nat Commun. 2015 Dec 22;6:10086. Tiao G et al. Rare germline variants in ATM are associated with chronic lymphocytic leukemia. Leukemia. 2017 Oct;31(10):2244-2247. Yurgelun MB et al. Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. J Clin Oncol. 2017 Apr 1;35(10):1086-1095.

#	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: Jan 26, 2021

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