NM_000051.4(ATM):c.6814G>A (p.Glu2272Lys) AND not provided

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Oct 14, 2021
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:: RCV000586472.16

Allele description [Variation Report for NM_000051.4(ATM):c.6814G>A (p.Glu2272Lys)]

NM_000051.4(ATM):c.6814G>A (p.Glu2272Lys)

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.6814G>A (p.Glu2272Lys)

HGVS:

NC_000011.10:g.108326064G>A
NG_009830.1:g.108233G>A
NG_054724.1:g.148769C>T
NM_000051.4:c.6814G>AMANE SELECT
NM_001330368.2:c.641-16993C>T
NM_001351110.2:c.*38+9156C>T
NM_001351834.2:c.6814G>A
NP_000042.3:p.Glu2272Lys
NP_000042.3:p.Glu2272Lys
NP_001338763.1:p.Glu2272Lys
LRG_135t1:c.6814G>A
LRG_135:g.108233G>A
LRG_135p1:p.Glu2272Lys
NC_000011.9:g.108196791G>A
NM_000051.3:c.6814G>A

Protein change:

E2272K

Links:

dbSNP: rs886039471

NCBI 1000 Genomes Browser:

rs886039471

Molecular consequence:

NM_001330368.2:c.641-16993C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.*38+9156C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000051.4:c.6814G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.6814G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000322063	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Nov 19, 2018)	germline	clinical testing	Citation Link,
SCV000694332	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Jun 20, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000708587	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Uncertain significance (May 12, 2017)	germline	clinical testing	Citation Link,
SCV002771727	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Uncertain significance (Oct 14, 2021)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12673804, 31050087, 26467025

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
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
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

ATM gene alterations in childhood acute lymphoblastic leukemias.

Gumy Pause F, Wacker P, Maillet P, Betts D, Sappino AP.

Hum Mutat. 2003 May;21(5):554. Erratum in: Hum Mutat. 2003 Sep;22(3):256.

PubMed [citation]

PMID:: 12673804

Functional classification of ATM variants in ataxia-telangiectasia patients.

Fiévet A, Bellanger D, Rieunier G, Dubois d'Enghien C, Sophie J, Calvas P, Carriere JP, Anheim M, Castrioto A, Flabeau O, Degos B, Ewenczyk C, Mahlaoui N, Touzot F, Suarez F, Hully M, Roubertie A, Aladjidi N, Tison F, Antoine-Poirel H, Dahan K, Doummar D, et al.

Hum Mutat. 2019 Oct;40(10):1713-1730. doi: 10.1002/humu.23778. Epub 2019 May 17.

PubMed [citation]

PMID:: 31050087

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000322063.8

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

Description

This variant is denoted ATM c.6814G>A at the cDNA level, p.Glu2272Lys (E2272K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant was observed in an individual with childhood acute lymphoblastic leukemia (Gumy Pause 2003). ATM Glu2272Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). ATM Glu2272Lys is located in the FAT domain (Stracker 2013). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether ATM Glu2272Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000694332.1

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

Description

Variant summary: The ATM c.6814G>A (p.Glu2272Lys) variant involves the alteration of a conserved nucleotide. The variant is present in RAD-3 domain however it is unknown whether the domain is critical to protein function or it involves a critical residue. 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). This variant is absent in 120880 control chromosomes. The variant was found as germline variant in one acute lymphoblastic leukemia sample and as somatic variant in one esophagus sample (Gumy Pause_2003, Lin_2014); however without strong evidence for causality. Because of the absence of sufficient clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.

#	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 Eurofins Ntd Llc (ga), SCV000708587.2

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

From Athena Diagnostics, SCV002771727.1

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

#	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

Last Updated: Nov 3, 2024

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