NM_000051.4(ATM):c.6154G>A (p.Glu2052Lys) AND Familial cancer of breast

Germline classification:: Conflicting classifications of pathogenicity (4 submissions)
Last evaluated:: Feb 29, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV001251135.17

Allele description [Variation Report for NM_000051.4(ATM):c.6154G>A (p.Glu2052Lys)]

NM_000051.4(ATM):c.6154G>A (p.Glu2052Lys)

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.6154G>A (p.Glu2052Lys)

Other names:

p.E2052K:GAA>AAA

HGVS:

NC_000011.10:g.108316069G>A
NG_009830.1:g.98238G>A
NG_054724.1:g.158764C>T
NM_000051.4:c.6154G>AMANE SELECT
NM_001330368.2:c.641-6998C>T
NM_001351110.2:c.*39-6998C>T
NM_001351834.2:c.6154G>A
NP_000042.3:p.Glu2052Lys
NP_000042.3:p.Glu2052Lys
NP_001338763.1:p.Glu2052Lys
LRG_135t1:c.6154G>A
LRG_135:g.98238G>A
LRG_135p1:p.Glu2052Lys
NC_000011.9:g.108186796G>A
NM_000051.3:c.6154G>A
NM_000051.3:c.6154G>A
p.E2052K

Protein change:

E2052K

Links:

dbSNP: rs202206540

NCBI 1000 Genomes Browser:

rs202206540

Molecular consequence:

NM_001330368.2:c.641-6998C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.*39-6998C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000051.4:c.6154G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.6154G>A - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001426633	Centogene AG - the Rare Disease Company	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25741868, 32860008
SCV003925623	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 3, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003936017	KCCC/NGS Laboratory, Kuwait Cancer Control Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 6, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004203838	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 29, 2024)	unknown	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	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

Citations

PubMed

Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort.

Bertoli-Avella AM, Beetz C, Ameziane N, Rocha ME, Guatibonza P, Pereira C, Calvo M, Herrera-Ordonez N, Segura-Castel M, Diego-Alvarez D, Zawada M, Kandaswamy KK, Werber M, Paknia O, Zielske S, Ugrinovski D, Warnack G, Kampe K, Iurașcu MI, Cozma C, Vogel F, Alhashem A, et al.

Eur J Hum Genet. 2021 Jan;29(1):141-153. doi: 10.1038/s41431-020-00713-9. Epub 2020 Aug 28.

PubMed [citation]

PMID:: 32860008
PMCID:: PMC7852664

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 Centogene AG - the Rare Disease Company, SCV001426633.1

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

#	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 of Human Genetics, University of Leipzig Medical Center, SCV003925623.1

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

Description

_x000D_ Criteria applied: PS4_MOD, 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 KCCC/NGS Laboratory, Kuwait Cancer Control Center, SCV003936017.2

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

Description

A likely pathogenic mutationsin the ATM gene (c.6154G>A). This sequence change results in a moderately conserved amino acid change located in the PIK-related kinase domain (IPR014009) of the encoded protein sequence. In-silico predictions show Pathogenic computational verdict based on 8 pathogenic predictions from DANN, EIGEN, FATHMM-MKL, LIST-S2, M-CAP, MVP, MutationAssessor and MutationTaster vs 4 benign predictions from BayesDel_addAF, DEOGEN2, PrimateAI and SIFT. The variant allele was found at a frequency of 5.7e-05 in 282788 control chromosomes, predominantly at a frequency of 0.0004 within the South Asian subpopulation in the gnomAD database. However, the variant was reported with an even higher frequency (0.001) in Indian subpopulations (Narang 2020). This variant, c.6154G>A, has been observed with a second pathogenic ATM variant in trans in several individuals who had a milder phenotype of ataxia telangiectasia (e.g. Charlesworth_2013, Necpal_2018, Rudenskaya_2019, Carecchio_2019); these patients typically had segmental dystonia in some cases with conjunctival telangiectasia, a phenotype corresponding to variant ataxia telangiectasia, characteristic to missense mutations that leave some residual ATM kinase activity (see e.g. PMID 30549301). The variant was also reported in several individuals with a personal and/or family history of breast and/or ovarian cancer or other tumor phenotypes (e.g. Kraus_2016, Singh_2018, Lu_2019, Adaniel_2019, Yadav_2020, Matejcic_2020), however in one of these reports a co-occurrence with a likely pathogenic variant (RAD51C c.404G>A, p.Cys135Tyr) has been described in an affected woman (breast and ovarian cancer) as well as in her daughter (thyroid cancer), providing supporting evidence for a benign role (Adaniel_2019). Therefore, this variant has been classified as likely pathogenic.

#	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, SCV004203838.2

#	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

Last Updated: Apr 20, 2025

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