NM_000051.4(ATM):c.742C>G (p.Arg248Gly) AND Ataxia-telangiectasia syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Dec 31, 2023
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:: RCV002601700.6

Allele description [Variation Report for NM_000051.4(ATM):c.742C>G (p.Arg248Gly)]

NM_000051.4(ATM):c.742C>G (p.Arg248Gly)

Gene:

ATM:ATM serine/threonine kinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q22.3

Genomic location:

Preferred name:

NM_000051.4(ATM):c.742C>G (p.Arg248Gly)

HGVS:

NC_000011.10:g.108244867C>G
NG_009830.1:g.27036C>G
NM_000051.4:c.742C>GMANE SELECT
NM_001351834.2:c.742C>G
NP_000042.3:p.Arg248Gly
NP_000042.3:p.Arg248Gly
NP_001338763.1:p.Arg248Gly
LRG_135t1:c.742C>G
LRG_135:g.27036C>G
LRG_135p1:p.Arg248Gly
NC_000011.9:g.108115594C>G
NM_000051.3:c.742C>G

Protein change:

R248G

Molecular consequence:

NM_000051.4:c.742C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.742C>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
SCV002949895	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 31, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 3149931, 28492532
SCV004047426	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002949895

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 31, 2023)

germline

clinical testing

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

SCV004047426

Neuberg Centre For Genomic Medicine, NCGM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic

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

Citations

PubMed

The molecular biology of cyanogenesis.

Hughes MA, Sharif AL, Dunn MA, Oxtoby E.

Ciba Found Symp. 1988;140:111-30. Review.

PubMed [citation]

PMID:: 3149931

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

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002949895.2

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

Description

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 248 of the ATM protein (p.Arg248Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cerebellar ataxia (PMID: 3149931). ClinVar contains an entry for this variant (Variation ID: 1917922). 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. 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.

#	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 Neuberg Centre For Genomic Medicine, NCGM, SCV004047426.1

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

Description

The missense variant c.742C>G (p.Arg248Gly) in ATM gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. However, another variant in the ATM gene at the same position c.742C>T (p.Arg248Ter) has been reported in individuals affected with ataxia telangiectasia (Sasaki et al. 1998, Mitui et al. 2005). The c.742C>T (p.Arg248Ter) variant creates a premature translational stop signal (p.Arg248*) in the ATM gene which is expected to result in an absent or disrupted protein product whereas the variant c.742C>G (p.Arg248Gly) causes a missense change. The c.742C>G (p.Arg248Gly) variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Arg at position 248 is changed to a Gly changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change c.742C>G (p.Arg248Gly) in ATM is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.

#	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

Last Updated: Sep 29, 2024

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