NM_000051.4(ATM):c.7475T>G (p.Leu2492Arg) AND not provided

Germline classification:: Uncertain significance (7 submissions)
Last evaluated:: Jun 14, 2023
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:: RCV000488003.34

Allele description [Variation Report for NM_000051.4(ATM):c.7475T>G (p.Leu2492Arg)]

NM_000051.4(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_000051.4(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_000051.4:c.7475T>GMANE SELECT
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_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
NM_000051.3:c.7475T>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_000051.4:c.7475T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.7475T>G - 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
SCV000149161	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Jun 14, 2023)	germline	clinical testing	Citation Link,
SCV000574909	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Uncertain significance (May 1, 2019)	germline	clinical testing	Citation Link,
SCV000706050	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Uncertain significance (Feb 21, 2017)	germline	clinical testing	Citation Link,
SCV001807307	Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus	no assertion criteria provided	Uncertain significance	germline	clinical testing
SCV001952801	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Uncertain significance	germline	clinical testing
SCV002010783	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 3, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002046107	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Jan 14, 2021)	unknown	clinical testing	PubMed (14) [See all records that cite these PMIDs] 32606146, 30441849, 20305132, 33471991, 28779002, 26787654, 30306255, 31159747, 17344846, 28652578, 28135145, 25980754, 26689913, 26467025

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	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	unknown	1	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

Germline Mutations in DNA Repair Genes in Patients With Metastatic Castration-resistant Prostate Cancer.

Holeckova K, Baluchova K, Hives M, Musak L, Kliment J Sr, Skerenova M.

In Vivo. 2020 Jul-Aug;34(4):1773-1778. doi: 10.21873/invivo.11971.

PubMed [citation]

PMID:: 32606146
PMCID:: PMC7439863

See all PubMed Citations (15)

Details of each submission

From GeneDx, SCV000149161.18

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

Description

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast, prostate, colon, and other cancers (Greenman et al., 2007; Lu et al., 2015; Decker et al., 2017; Tiao et al., 2017; Yurgelun et al., 2017; Bonache et al., 2018; Hauke et al., 2018; Koczkowska et al., 2018; Yehia et al., 2018; Holeckova et al., 2020; Mangolini et al., 2022; Paduano et al., 2022; Andrikopoulou et al., 2022); This variant is associated with the following publications: (PMID: 35347810, 35127508, 35886069, 22529920, 17344846, 26689913, 25980754, 26787654, 22173549, 28873162, 28135145, 28652578, 26206375, 29522266, 28779002, 29684080, 30306255, 31159747, 31422574, 20305132, 30441849, 31920950, 32606146, 35047863, 36011273, 34284872, 23532176, 34718612)

#	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 CeGaT Center for Human Genetics Tuebingen, SCV000574909.26

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	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		2	not provided	not provided	not provided

From Eurofins Ntd Llc (ga), SCV000706050.2

#	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 Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus, SCV001807307.1

#	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 Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001952801.1

#	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 Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden, SCV002010783.3

#	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	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV002046107.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

Description

In the published literature, this variant has been reported in a control individual and in individuals affected with breast cancer (PMID: 30306255 (2018), 28779002 (2017), 20305132 (2010)), ovarian cancer (PMID: 30441849 (2018)), lung adenocarcinoma (PMID: 17344846 (2007)), chronic lymphocytic leukemia (PMID: 28652578 (2017)), glioblastoma (PMID: 26689913 (2015)), prostate cancer (PMID: 32606146 (2020)), and Lynch syndrome-associated cancer and/or polyps (PMID: 28135145 (2017), 25980754 (2015)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/ATM)). The frequency of this variant in the general population, 0.00039 (13/33062 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

#	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: Apr 20, 2024

Relating variation to medicine