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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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000149151GeneDx
criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)		Likely pathogenic
(Feb 28, 2024) 		germlineclinical testing

Citation Link,

SCV002064367Genetic Services Laboratory, University of Chicago
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Jun 11, 2019) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical 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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot 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)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 3, 2024