NM_000051.4(ATM):c.8494C>T (p.Arg2832Cys) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Dec 17, 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:: RCV000115265.24

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)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

Recent activity

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Saccharomyces cerevisiae S288C thiamine transporter TPC1 (TPC1), partial mRNA
Saccharomyces cerevisiae S288C thiamine transporter TPC1 (TPC1), partial mRNA
gi|398365650|ref|NM_001181225.3|

Nucleotide
cytochrome c oxidase subunit I (mitochondrion) [Polyplectron germaini]
cytochrome c oxidase subunit I (mitochondrion) [Polyplectron germaini]
gi|570700674|ref|YP_008994670.1|

Protein
asparaginase ASP3-1 [Saccharomyces cerevisiae S288C]
asparaginase ASP3-1 [Saccharomyces cerevisiae S288C]
gi|6323184|ref|NP_013256.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000186811	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Dec 17, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26022348, 28195393 Citation Link,
SCV000682491	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 8, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001448937	Knight Diagnostic Laboratories, Oregon Health and Sciences University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 26, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002527352	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Pathogenic (Jul 23, 2021)	germline	curation	PubMed (5) [See all records that cite these PMIDs] 9443866, 18634022, 21665257, 30093976, 33471991 Citation Link

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Summary from all submissions

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

Citations

PubMed

HBOC multi-gene panel testing: comparison of two sequencing centers.

Schroeder C, Faust U, Sturm M, Hackmann K, Grundmann K, Harmuth F, Bosse K, Kehrer M, Benkert T, Klink B, Mackenroth L, Betcheva-Krajcir E, Wimberger P, Kast K, Heilig M, Nguyen HP, Riess O, Schröck E, Bauer P, Rump A.

Breast Cancer Res Treat. 2015 Jul;152(1):129-136. doi: 10.1007/s10549-015-3429-9. Epub 2015 May 29.

PubMed [citation]

PMID:: 26022348

Use of multigene-panel identifies pathogenic variants in several CRC-predisposing genes in patients previously tested for Lynch Syndrome.

Hansen MF, Johansen J, Sylvander AE, Bjørnevoll I, Talseth-Palmer BA, Lavik LAS, Xavier A, Engebretsen LF, Scott RJ, Drabløs F, Sjursen W.

Clin Genet. 2017 Oct;92(4):405-414. doi: 10.1111/cge.12994. Epub 2017 Mar 22.

PubMed [citation]

PMID:: 28195393

See all PubMed Citations (8)

Details of each submission

From Ambry Genetics, SCV000186811.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.R2832C pathogenic mutation (also known as c.8494C>T), located in coding exon 57 of the ATM gene, results from a C to T substitution at nucleotide position 8494. The arginine at codon 2832 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected both as the only mutation and in conjunction with a second mutation in many ataxia-telangiectasia (A-T) patients (Telatar M et al. Am. J. Hum. Genet. 1998 Jan;62:86-97; Li A and Swift M. Am. J. Med. Genet. 2000 May;92:170-7; Becker-Catania SG et al. Mol. Genet. Metab. 2000 Jun;70:122-33; Mitui M et al. Hum. Mutat. 2009 Jan;30:12-21). Functional analyses of p.R2832C have shown abolished kinase activity, reduced protein levels, and increased radiosensitivity compared to wild type ATM. In addition, four of five mild A-T patients carrying this alteration developed cancer, including breast cancers, melanoma, and hematologic malignancies. Three of four p.R2832C carrier mothers from these families developed breast cancer (Mitui M et al. Hum. Mutat. 2009 Jan;30:12-21). It was also seen in a patient with a personal and family history of colorectal cancer (Hansen MF et al. Clin. Genet. 2017 Oct;92:405-414). Of note, this alteration is also designated as R2831C in published literature. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	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 Color Diagnostics, LLC DBA Color Health, SCV000682491.3

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

Description

This missense variant replaces arginine with cysteine at codon 2832 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in significantly reduced ATM protein expression and kinase activity, and intermediate radiosensitivity (PMID: 10873394, 18634022, 19431188, 22017321). This variant has also been observed homozygous or in compound heterozygous state with another pathogenic variant in individuals affected with ataxia-telangiectasia (PMID: 9443866, 10817650, 10873394, 12552559, 12673797, 18634022, 19147735, 19431188, 21792198, 22017321). This variant has also been reported in individuals affected with breast cancer (PMID: 18634022, 20301790, 26022348, 26681312, 28008555, 29665859, 30093976). This variant has been identified in 8/251268 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

#	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 Knight Diagnostic Laboratories, Oregon Health and Sciences University, SCV001448937.1

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

From Sema4, Sema4, SCV002527352.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (5)

#	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

Last Updated: Nov 3, 2024

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