NM_000051.4(ATM):c.8494C>T (p.Arg2832Cys) AND Familial cancer of breast

Germline classification:: Likely pathogenic (5 submissions)
Last evaluated:: Jan 25, 2024
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV001197256.15

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]

Condition(s)

Name:: Familial cancer of breast
Synonyms:: Breast cancer, familial; Hereditary breast cancer
Identifiers:: MONDO: MONDO:0016419; MedGen: C0346153; OMIM: 114480

Recent activity

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Defensin beta 6 [Mus musculus]
Defensin beta 6 [Mus musculus]
gi|111601336|gb|AAI19424.1|

Protein
Naumovozyma dairenensis CBS 421 chromosome 2, complete genome
Naumovozyma dairenensis CBS 421 chromosome 2, complete genome
gi|365984159|ref|NC_016480.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001367893	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 1, 2016)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001499612	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 2, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004209520	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 27, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004565390	ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen HBOP ACMG Specifications ATM V1.2.0)	Likely Pathogenic (Jan 25, 2024)	germline	curation	Citation Link,
SCV004933083	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Likely pathogenic (Feb 2, 2024)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 18634022, 21792198, 10873394, 21665257 Citation Link

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Summary from all submissions

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

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

Functional and computational assessment of missense variants in the ataxia-telangiectasia mutated (ATM) gene: mutations with increased cancer risk.

Mitui M, Nahas SA, Du LT, Yang Z, Lai CH, Nakamura K, Arroyo S, Scott S, Purayidom A, Concannon P, Lavin M, Gatti RA.

Hum Mutat. 2009 Jan;30(1):12-21. doi: 10.1002/humu.20805.

PubMed [citation]

PMID:: 18634022
PMCID:: PMC2776735

See all PubMed Citations (5)

Details of each submission

From Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV001367893.2

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

Description

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM2,PP4,PP3.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Department of Molecular Diagnostics, Institute of Oncology Ljubljana, SCV001499612.1

#	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

From Baylor Genetics, SCV004209520.2

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

From ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen, SCV004565390.1

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

Description

The c.8494C>T variant in ATM is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 2832 (p.Arg2832Cys). This variant has been detected in at least 3 individuals with Ataxia-Telangiectasia (PMID: 26896183, 22017321, 26846839). The highest minor allele frequency in gnomAD v2.1.1 of 0.01% (2/16244 alleles) in the African/African American population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor, Revel (Score: 0.83), predicts a damaging effect on ATM function. Additionally, experimental studies showed that this variant has impact on ATM kinase activity and protein levels but radiosensitivity was found to be intermediate compared to wild type (PMID: 18634022). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PM3_Strong, PP3, PS3_supporting)

#	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 Myriad Genetics, Inc., SCV004933083.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 18634022, 21792198]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 10873394, 21665257].

#	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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