NM_000051.4(ATM):c.2127T>C (p.Ile709=) AND not specified

Germline classification:: Benign (5 submissions)
Last evaluated:: Oct 27, 2020
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:: RCV000211973.8

Allele description [Variation Report for NM_000051.4(ATM):c.2127T>C (p.Ile709=)]

NM_000051.4(ATM):c.2127T>C (p.Ile709=)

Gene:

ATM:ATM serine/threonine kinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q22.3

Genomic location:

Preferred name:

NM_000051.4(ATM):c.2127T>C (p.Ile709=)

Other names:

p.I709I:ATT>ATC

HGVS:

NC_000011.10:g.108256217T>C
NG_009830.1:g.38386T>C
NM_000051.4:c.2127T>CMANE SELECT
NM_001351834.2:c.2127T>C
NP_000042.3:p.Ile709=
NP_000042.3:p.Ile709=
NP_001338763.1:p.Ile709=
LRG_135t1:c.2127T>C
LRG_135:g.38386T>C
LRG_135p1:p.Ile709=
NC_000011.9:g.108126944T>C
NM_000051.3:c.2127T>C
p.I709I

Links:

dbSNP: rs56252953

NCBI 1000 Genomes Browser:

rs56252953

Molecular consequence:

NM_000051.4:c.2127T>C - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001351834.2:c.2127T>C - synonymous variant - [Sequence Ontology: SO:0001819]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000167070	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Benign (Dec 31, 2013)	germline	clinical testing	Citation Link,
SCV000918556	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (Aug 3, 2018)	germline	clinical testing	Citation Link,
SCV001552750	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Benign	unknown	clinical testing
SCV002070661	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (May 3, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002774010	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Benign (Oct 27, 2020)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 12969974, 26467025

Help

Summary from all submissions

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

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

Identification and characterization of polymorphic variations of the ataxia telangiectasia mutated (ATM) gene in childhood Hodgkin disease.

Takagi M, Tsuchida R, Oguchi K, Shigeta T, Nakada S, Shimizu K, Ohki M, Delia D, Chessa L, Taya Y, Nakanishi M, Tsunematsu Y, Bessho F, Isoyama K, Hayashi Y, Kudo K, Okamura J, Mizutani S.

Blood. 2004 Jan 1;103(1):283-90. Epub 2003 Sep 11.

PubMed [citation]

PMID:: 12969974

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000167070.11

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

Description

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000918556.1

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

Description

Variant summary: ATM c.2127T>C (p.Ile709Ile) alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0013 in 275790 control chromosomes, predominantly at a frequency of 0.019 within the East Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 18.99 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.2127T>C in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as benign.

#	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 Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001552750.1

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

Description

The ATM p.Ile709= variant was identified in 2 of 200 proband chromosomes (frequency: 0.01) from individuals or families with Hodgkin Disease from Canadian and Japanese pediatric patients, and was not identified in 200 control chromosomes from healthy individuals (Sipahimalani 2007, Takagi 2017). The variant was also identified in dbSNP (ID: rs56252953) as â€šÃ„Ãºwith uncertain significance, other alleleâ€šÃ„Ã¹; in ClinVar and Clinvitae databases as benign by Invitae, GeneDx, as likely benign by Ambry Genetics and as uncertain significance by Illumina Clinical Services. In addition, the variant was identified in the 1000 Genomes Project in 8 of 5000 chromosomes (frequency: 0.002). The variant was identified in control databases in 354 (1 homozygous) of 275790 chromosomes at a frequency of 0.001 in the following populations: East Asian in 351of 18624 chromosomes (freq. 0.02), South Asian in 1 of 30600 chromosomes (freq. 0.00003), other in 2 of 6418 chromosomes (freq. 0.0003), but was not seen in African, Latino, European Non-Finnish, Ashkenazi Jewish, and European Finnish populations, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The variant was not identified in Cosmic, MutDB, LOVD 3.0, ATM-LOVD, databases or in the NHLBI GO Exome Sequencing Project. The p.Ile709Ile variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.

#	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 Genetic Services Laboratory, University of Chicago, SCV002070661.1

#	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	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV002774010.1

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

Last Updated: Feb 28, 2024

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