NM_000051.4(ATM):c.3014A>G (p.Asn1005Ser) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Aug 1, 2022
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:: RCV000588986.29

Allele description [Variation Report for NM_000051.4(ATM):c.3014A>G (p.Asn1005Ser)]

NM_000051.4(ATM):c.3014A>G (p.Asn1005Ser)

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.3014A>G (p.Asn1005Ser)

Other names:

p.N1005S:AAT>AGT

HGVS:

NC_000011.10:g.108271343A>G
NG_009830.1:g.53512A>G
NM_000051.4:c.3014A>GMANE SELECT
NM_001351834.2:c.3014A>G
NP_000042.3:p.Asn1005Ser
NP_000042.3:p.Asn1005Ser
NP_001338763.1:p.Asn1005Ser
LRG_135t1:c.3014A>G
LRG_135:g.53512A>G
LRG_135p1:p.Asn1005Ser
NC_000011.9:g.108142070A>G
NM_000051.3:c.3014A>G
p.N1005S

Protein change:

N1005S

Links:

dbSNP: rs146531614

NCBI 1000 Genomes Browser:

rs146531614

Molecular consequence:

NM_000051.4:c.3014A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.3014A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000149080	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Nov 14, 2017)	germline	clinical testing	Citation Link,
SCV000340770	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Uncertain significance (Mar 29, 2016)	germline	clinical testing	Citation Link,
SCV001749644	GenomeConnect - Invitae Patient Insights Network	no classification provided	not provided	unknown	phenotyping only
SCV002544606	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely benign (Aug 1, 2022)	germline	clinical testing	Citation Link,
SCV004220910	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Benign (May 6, 2022)	unknown	clinical testing	PubMed (9) [See all records that cite these PMIDs] 25479140, 23555315, 33395407, 29522266, 28779002, 26976419, 26689913, 30883245, 26467025

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	3	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, phenotyping only
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer.

Grant RC, Selander I, Connor AA, Selvarajah S, Borgida A, Briollais L, Petersen GM, Lerner-Ellis J, Holter S, Gallinger S.

Gastroenterology. 2015 Mar;148(3):556-64. doi: 10.1053/j.gastro.2014.11.042. Epub 2014 Dec 2.

PubMed [citation]

PMID:: 25479140
PMCID:: PMC4339623

Genome-wide testing of putative functional exonic variants in relationship with breast and prostate cancer risk in a multiethnic population.

Haiman CA, Han Y, Feng Y, Xia L, Hsu C, Sheng X, Pooler LC, Patel Y, Kolonel LN, Carter E, Park K, Le Marchand L, Van Den Berg D, Henderson BE, Stram DO.

PLoS Genet. 2013 Mar;9(3):e1003419. doi: 10.1371/journal.pgen.1003419. Epub 2013 Mar 28.

PubMed [citation]

PMID:: 23555315
PMCID:: PMC3610631

See all PubMed Citations (9)

Details of each submission

From GeneDx, SCV000149080.14

#	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.3014A>G at the cDNA level, p.Asn1005Ser (N1005S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant has been reported in individuals with personal histories of breast, ovarian, and pancreatic cancer (Grant 2015, Lu 2015, Tung 2016, Decker 2017). This variant was reported in a multiethnic exome array study; however, no statistically significant association with breast cancer was identified after correcting for multiple comparisons (Haiman 2013). ATM Asn1005Ser was observed at an allele frequency of 0.65% (66/10,142 alleles) in individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek 2016). This variant is located within the beta-adaptin interaction domain (Tavtigian 2009). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Asn1005Ser 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 Eurofins Ntd Llc (ga), SCV000340770.4

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

From GenomeConnect - Invitae Patient Insights Network, SCV001749644.1

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

Description

Variant interpreted as Benign and reported on 03-08-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

#	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 CeGaT Center for Human Genetics Tuebingen, SCV002544606.10

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

Description

ATM: BP1, BP4

#	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		3	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV004220910.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

#	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 15, 2024

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