NM_000051.4(ATM):c.7181C>T (p.Ser2394Leu) AND not provided

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Feb 28, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000115242.19

Allele description [Variation Report for NM_000051.4(ATM):c.7181C>T (p.Ser2394Leu)]

NM_000051.4(ATM):c.7181C>T (p.Ser2394Leu)

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.7181C>T (p.Ser2394Leu)

Other names:

p.S2394L:TCA>TTA

HGVS:

NC_000011.10:g.108329112C>T
NG_009830.1:g.111281C>T
NG_054724.1:g.145721G>A
NM_000051.4:c.7181C>TMANE SELECT
NM_001330368.2:c.641-20041G>A
NM_001351110.2:c.*38+6108G>A
NM_001351834.2:c.7181C>T
NP_000042.3:p.Ser2394Leu
NP_000042.3:p.Ser2394Leu
NP_001338763.1:p.Ser2394Leu
LRG_135t1:c.7181C>T
LRG_135:g.111281C>T
LRG_135p1:p.Ser2394Leu
NC_000011.9:g.108199839C>T
NM_000051.3:c.7181C>T

Protein change:

S2394L

Links:

dbSNP: rs587779861

NCBI 1000 Genomes Browser:

rs587779861

Molecular consequence:

NM_001330368.2:c.641-20041G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.*38+6108G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000051.4:c.7181C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.7181C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000149151	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Feb 28, 2024)	germline	clinical testing	Citation Link,
SCV002064367	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 11, 2019)	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

SCV000149151

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Feb 28, 2024)

germline

clinical testing

Citation Link,

SCV002064367

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jun 11, 2019)

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From GeneDx, SCV000149151.19

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

Description

Observed with a pathogenic variant on the opposite allele (in trans) in a patient with atypical ataxia telangiectasia (PMID: 26677768); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19431188, 26681312, 32647791, 18573109, no PMID, 26677768, 23532176)

#	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 Genetic Services Laboratory, University of Chicago, SCV002064367.1

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

Description

The second sequence change, c.7181C>T, in exon 49 results in an amino acid change, p.Ser2394Leu. The p.Ser2394Leu change affects a moderately conserved amino acid residue located in a domain of the ATM protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ser2394Leu substitution. This particular amino acid change has been described in the literature in one female patient with Ataxia-telangiectasia along with another pathogenic change (Lin et al., 2015). In vitro expression studies have shown that the resulting p.Ser2394Leu protein has absent ATM kinase activity (Barone et al., 2009 and Austen et al., 2008). This sequence change has not been described in the population databases (ExAC and gnomAD). These collective evidences indicate that this sequence change is likely pathogenic. This sequence change was identified with another pathogenic ATM variant in a patient.

#	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 16, 2024

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