NM_000051.4(ATM):c.4066A>G (p.Asn1356Asp) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (6 submissions)
Last evaluated:: Oct 1, 2023
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:: RCV000586490.45

Allele description [Variation Report for NM_000051.4(ATM):c.4066A>G (p.Asn1356Asp)]

NM_000051.4(ATM):c.4066A>G (p.Asn1356Asp)

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.4066A>G (p.Asn1356Asp)

Other names:

p.N1356D:AAT>GAT

HGVS:

NC_000011.10:g.108287672A>G
NG_009830.1:g.69841A>G
NM_000051.4:c.4066A>GMANE SELECT
NM_001351834.2:c.4066A>G
NP_000042.3:p.Asn1356Asp
NP_000042.3:p.Asn1356Asp
NP_001338763.1:p.Asn1356Asp
LRG_135t1:c.4066A>G
LRG_135:g.69841A>G
LRG_135p1:p.Asn1356Asp
NC_000011.9:g.108158399A>G
NM_000051.3:c.4066A>G
p.N1356D

Protein change:

N1356D

Links:

dbSNP: rs147600485

NCBI 1000 Genomes Browser:

rs147600485

Molecular consequence:

NM_000051.4:c.4066A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.4066A>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
SCV000149094	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely benign (Aug 4, 2022)	germline	clinical testing	Citation Link,
SCV000840937	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics criteria)	Uncertain significance (Oct 26, 2020)	unknown	clinical testing	PubMed (11) [See all records that cite these PMIDs] 12935922, 19781682, 26689913, 25980754, 26898890, 28779002, 30938815, 25186627, 21787400, 30181556, 26467025
SCV001148418	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely benign (Oct 1, 2023)	germline	clinical testing	Citation Link,
SCV001473120	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Uncertain significance (Dec 28, 2019)	germline	clinical testing	Citation Link,
SCV001713575	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 16, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002047333	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Mar 21, 2023)	unknown	clinical testing	PubMed (14) [See all records that cite these PMIDs] 12935922, 19781682, 26689913, 25980754, 26898890, 28779002, 34262154, 33471991, 35047863, 30938815, 25186627, 21787400, 30181556, 26467025

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	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	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 missense mutations are frequent in patients with breast cancer.

Sommer SS, Jiang Z, Feng J, Buzin CH, Zheng J, Longmate J, Jung M, Moulds J, Dritschilo A.

Cancer Genet Cytogenet. 2003 Sep;145(2):115-20.

PubMed [citation]

PMID:: 12935922

See all PubMed Citations (15)

Details of each submission

From GeneDx, SCV000149094.15

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

Description

See Variant Classification Assertion Criteria.

#	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 Athena Diagnostics, SCV000840937.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

#	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, SCV001148418.27

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

Description

ATM: 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		2	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001473120.1

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

Description

The ATM c.4066A>G; p.Asn1356Asp variant (rs147600485) is reported in the literature in individuals with breast cancer (Sommer 2003, Tavtigian 2009, Tung 2015), and Lynch syndrome (Yurgelun 2015); however, this variant co-occurred with a pathogenic MSH2 deletion of exons 8-15 (Yurgelun 2015). This variant is also reported in ClinVar (Variation ID: 127380). It is found in the general population with an overall allele frequency of 0.01% (39/280160 alleles) in the Genome Aggregation Database. The asparagine at codon 1356 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Sommer SS et al. ATM missense mutations are frequent in patients with breast cancer. Cancer Genet Cytogenet. 2003 Sep;145(2):115-20. Tavtigian SV et al. Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer. Am J Hum Genet. 2009 Oct;85(4):427-46. Tung N et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer. 2015 Jan 1;121(1):25-33. Yurgelun MB et al. Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. Gastroenterology. 2015 Sep;149(3):604-13.e20.

#	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 Mayo Clinic Laboratories, Mayo Clinic, SCV001713575.1

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

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV002047333.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

Description

In the published literature, this variant has been reported in individuals with breast cancer (PMIDs: 33471991 (2021); LOVD3 Shared (https://databases.lovd.nl/shared/), 30938815 (2019), 28779002 (2017), 26898890 (2016), 19781682 (2009), and 12935922 (2003)), pancreatic cancer (PMID: 35047863 (2022)), and melanoma (PMID: 34262154 (2021)). The variant has also been reported in unaffected individuals (PMIDs: 35047863 (2022), 33471991 (2021); LOVD3 Shared (https://databases.lovd.nl/shared/), 28779002 (2017), 19781682 (2009), and FLOSSIES database (https://whi.color.com/)). In an individual undergoing multigene panel testing for suspected Lynch syndrome, this variant was reported to co-occur with a pathogenic variant in the MSH2 gene (PMID: 25980754 (2015)). The frequency of this variant in the general population, 0.00041 (20/48670 chromosomes in North-Western European subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.

#	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 10, 2024

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