NM_000051.3(ATM):c.8156G>A (p.Arg2719His) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 7, 2018
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:: RCV000586113.1

Allele description

NM_000051.3(ATM):c.8156G>A (p.Arg2719His)

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_000051.3(ATM):c.8156G>A (p.Arg2719His)

Other names:

p.R2719H:CGT>CAT

HGVS:

NC_000011.10:g.108335849G>A
NG_009830.1:g.118018G>A
NG_054724.1:g.138984C>T
NM_000051.3:c.8156G>A
NM_001330368.2:c.641-26778C>T
NM_001351110.2:c.695-557C>T
NM_001351834.2:c.8156G>A
NP_000042.3:p.Arg2719His
NP_001338763.1:p.Arg2719His
LRG_135t1:c.8156G>A
LRG_135:g.118018G>A
LRG_135p1:p.Arg2719His
NC_000011.9:g.108206576G>A
Q13315:p.Arg2719His
p.R2719H

Protein change:

R2719H

Links:

UniProtKB: Q13315#VAR_041581; dbSNP: rs55982963

NCBI 1000 Genomes Browser:

rs55982963

Molecular consequence:

NM_001330368.2:c.641-26778C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.695-557C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000051.3:c.8156G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.8156G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Identifiers:: MedGen: CN517202

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000149171	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Nov 7, 2018)	germline	clinical testing	Citation Link,
SCV000694372	Integrated Genetics/Laboratory Corporation of America	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Feb 16, 2017)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22529920, 21445571, 19781682, 18384426 LabCorp Variant Classification Summary - May 2015.docx Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000149171

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Nov 7, 2018)

germline

clinical testing

Citation Link,

SCV000694372

Integrated Genetics/Laboratory Corporation of America

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Feb 16, 2017)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	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

Computational refinement of functional single nucleotide polymorphisms associated with ATM gene.

George Priya Doss C, Rajith B.

PLoS One. 2012;7(4):e34573. doi: 10.1371/journal.pone.0034573. Epub 2012 Apr 13.

PubMed [citation]

PMID:: 22529920
PMCID:: PMC3326031

Germline ATM mutational analysis in BRCA1/BRCA2 negative hereditary breast cancer families by MALDI-TOF mass spectrometry.

Graña B, Fachal L, Darder E, Balmaña J, Ramón Y Cajal T, Blanco I, Torres A, Lázaro C, Diez O, Alonso C, Santamariña M, Velasco A, Teulé A, Lasa A, Blanco A, Izquierdo A, Borràs J, Gutiérrez-Enríquez S, Vega A, Brunet J.

Breast Cancer Res Treat. 2011 Jul;128(2):573-9. doi: 10.1007/s10549-011-1462-x. Epub 2011 Mar 29.

PubMed [citation]

PMID:: 21445571

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000149171.14

#	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 denoted ATM c.8156G>A at the cDNA level, p.Arg2719His (R2719H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant has been reported in individuals with suspected hereditary breast/ovarian cancer as well as in an individual with urothelial bladder cancer (Brunet 2008, Balb?s-Mart?nez 2013, Maxwell 2016, Mucaki 2016). ATM Arg2719His was observed at an allele frequency of 0.051%, (17/33,528) in individuals of Latino ancestry in large population cohorts (Lek 2016). ATM Arg2719His is located in the ATP binding domain within the kinase domain (Lavin 2004, Stracker 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Arg2719His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

#	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 Integrated Genetics/Laboratory Corporation of America, SCV000694372.1

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

Description

Variant summary: The c.8156G>A (p.Arg2719His) in ATM gene is a missense change that involves a conserved nucleotide and 4/5 in silico tools predict deleterious outcome. The variant is located in the PI3/PI4-kinase domain, however no functional studies confirming deleterious effect of this change have been reported at the time of evaluation. The variant is present in the control population dataset of ExAC at a frequency of 0.00017 (20/116502 chrs tested), predominantly in individuals of Latino descent (0.0017; 13/1130chrs tested), including 1 homozygote. The latter frequency exceeds the maximum expected allele frequency for a pathogenic variant of 0.0010, suggesting it is may be an ethnic-specific functional polymorphism. The variant has been reported in BrC pts without strong evidence for causality. The variant is cited as VUS by a reputable databases/clinical laboratories without evidence to independently evaluate. Taking together, the variant was classified as VUS.

#	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 7, 2019

ClinVar

Relating variation to medicine