NM_000051.4(ATM):c.8494C>T (p.Arg2832Cys) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Jul 31, 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:: RCV000212084.26

Allele description [Variation Report for NM_000051.4(ATM):c.8494C>T (p.Arg2832Cys)]

NM_000051.4(ATM):c.8494C>T (p.Arg2832Cys)

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.8494C>T (p.Arg2832Cys)

Other names:

p.R2832C:CGT>TGT; NM_000051.4(ATM):c.8494C>T

HGVS:

NC_000011.10:g.108345818C>T
NG_009830.1:g.127987C>T
NG_054724.1:g.129015G>A
NM_000051.4:c.8494C>TMANE SELECT
NM_001330368.2:c.641-36747G>A
NM_001351110.2:c.695-10526G>A
NM_001351834.2:c.8494C>T
NP_000042.3:p.Arg2832Cys
NP_000042.3:p.Arg2832Cys
NP_001338763.1:p.Arg2832Cys
LRG_135t1:c.8494C>T
LRG_135:g.127987C>T
LRG_135p1:p.Arg2832Cys
NC_000011.9:g.108216545C>T
NM_000051.3:c.8494C>T
NM_000051.3:c.8494C>T
Q13315:p.Arg2832Cys
p.R2832C

Protein change:

R2832C

Links:

UniProtKB: Q13315#VAR_010881; dbSNP: rs587779872

NCBI 1000 Genomes Browser:

rs587779872

Molecular consequence:

NM_001330368.2:c.641-36747G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.695-10526G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000051.4:c.8494C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.8494C>T - 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
SCV000149174	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (May 24, 2023)	germline	clinical testing	Citation Link,
SCV001963400	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001968972	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV004042529	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely pathogenic (Sep 1, 2023)	germline	clinical testing	Citation Link,
SCV005089831	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 31, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005196929	Clinical Genetics Laboratory, Skane University Hospital Lund	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 27, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

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

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, SCV000149174.17

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

Description

Published functional studies demonstrate a damaging effect: reduced ATM protein levels and reduced or absent ATM kinase activity (Becker-Catania et al., 2000; Sun et al., 2002; Butch et al., 2004; Chun and Gatti, 2004; Barone et al., 2009; Mitui et al., 2009; Reiman et al., 2011; Fievet et al., 2019; Schon et al., 2019); Observed in the heterozygous state in individuals with ATM-related cancers (Schroeder et al., 2015; Hansen et al., 2017; Renault et al., 2018; Girard et al., 2019); 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: 15503472, 25793145, 9443866, 16448697, 29665859, 32980694, 29922827, 28888541, 12673797, 12072877, 20301790, 23091097, 15486025, 19431188, 10817650, 25040471, 12497634, 18634022, 15279807, 27135926, 26681312, 26312527, 26022348, 28008555, 28195393, 12552559, 22529920, 25827173, 30093976, 30549301, 31050087, 21792198, 22017321, 23532176, 29625052, 30875412, 35264596, 34926252, 35737913, 33328602, 35486574, 33471991, 32155193, 36988593, 35454905, 35365198, 36521553, 26896183, 26846839, 21665257, 10873394, 30303537)

#	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 Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001963400.1

#	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 Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001968972.1

#	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 CeGaT Center for Human Genetics Tuebingen, SCV004042529.11

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

Description

ATM: PM1, PM2, PM5, PS3:Moderate, BP1

#	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		1	not provided	not provided	not provided

From Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV005089831.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics Laboratory, Skane University Hospital Lund, SCV005196929.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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