NM_000051.4(ATM):c.6095G>A (p.Arg2032Lys) AND Familial cancer of breast

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Mar 29, 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:: RCV000709711.18

Allele description [Variation Report for NM_000051.4(ATM):c.6095G>A (p.Arg2032Lys)]

NM_000051.4(ATM):c.6095G>A (p.Arg2032Lys)

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.6095G>A (p.Arg2032Lys)

Other names:

p.R2032K:AGA>AAA

HGVS:

NC_000011.10:g.108315911G>A
NG_009830.1:g.98080G>A
NG_054724.1:g.158922C>T
NM_000051.4:c.6095G>AMANE SELECT
NM_001330368.2:c.641-6840C>T
NM_001351110.2:c.*39-6840C>T
NM_001351834.2:c.6095G>A
NP_000042.3:p.Arg2032Lys
NP_000042.3:p.Arg2032Lys
NP_001338763.1:p.Arg2032Lys
LRG_135t1:c.6095G>A
LRG_135:g.98080G>A
LRG_135p1:p.Arg2032Lys
NC_000011.9:g.108186638G>A
NM_000051.3:c.6095G>A
p.R2032K

Protein change:

R2032K

Links:

dbSNP: rs139770721

NCBI 1000 Genomes Browser:

rs139770721

Molecular consequence:

NM_001330368.2:c.641-6840C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.*39-6840C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000051.4:c.6095G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.6095G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000839886	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 30, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001367968	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 9, 2022)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV001499611	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]
SCV002588955	BRCAlab, Lund University	no assertion criteria provided	Pathogenic (Aug 26, 2022)	germline	clinical testing
SCV004176013	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 15, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004210046	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 29, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004931300	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Likely pathogenic (Jan 29, 2024)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16266405, 9887333, 10330348 Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	3	not provided	not provided	not provided	clinical testing
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

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

ATM gene founder haplotypes and associated mutations in Polish families with ataxia-telangiectasia.

Mitui M, Bernatowska E, Pietrucha B, Piotrowska-Jastrzebska J, Eng L, Nahas S, Teraoka S, Sholty G, Purayidom A, Concannon P, Gatti RA.

Ann Hum Genet. 2005 Nov;69(Pt 6):657-64.

PubMed [citation]

PMID:: 16266405

See all PubMed Citations (4)

Details of each submission

From Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV000839886.1

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

Description

This c.6095G>A (p.R2032K) variant in the ATM gene has been reported in multiple Ataxia-telangiectasia (AT) patients with significantly higher prevalence [PMID: 10980530, 15390180,16266405] than that observed as extremely low in general population according to gnomad database. This variant, in trans with other deleterious variants, has been reported in AT patients [PMID: 27159176, 25614872]. Functional studies showed that this mutant causes abnormal splicing and loss of expression of ATM proteins [PMID: 9887333, 10330348]. Multiple in silico predictions suggest this arginine to lysine is deleterious, while the c.6095G>A change might affect the splicing of messenger RNA as the last nucleotide on exon 41. Based upon above evidences, this c.6095G>A (p.R2032K) variant in the ATM gene 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 Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV001367968.4

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

Description

PS3_MOD, PM3_VSTR

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Department of Molecular Diagnostics, Institute of Oncology Ljubljana, SCV001499611.1

#	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 BRCAlab, Lund University, SCV002588955.1

#	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	3	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV004176013.1

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

Description

Criteria applied: PVS1,PM3,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 Baylor Genetics, SCV004210046.2

#	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 Myriad Genetics, Inc., SCV004931300.1

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

Description

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 16266405]. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 9887333, 10330348].

#	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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