NM_000051.4(ATM):c.6537T>G (p.Ile2179Met) AND not provided

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Mar 13, 2024
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:: RCV000590569.23

Allele description [Variation Report for NM_000051.4(ATM):c.6537T>G (p.Ile2179Met)]

NM_000051.4(ATM):c.6537T>G (p.Ile2179Met)

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.6537T>G (p.Ile2179Met)

Other names:

NP_000042.3:p.Ile2179Met

HGVS:

NC_000011.10:g.108321385T>G
NG_009830.1:g.103554T>G
NG_054724.1:g.153448A>C
NM_000051.4:c.6537T>GMANE SELECT
NM_001330368.2:c.641-12314A>C
NM_001351110.2:c.*39-12314A>C
NM_001351834.2:c.6537T>G
NP_000042.3:p.Ile2179Met
NP_000042.3:p.Ile2179Met
NP_001338763.1:p.Ile2179Met
LRG_135t1:c.6537T>G
LRG_135:g.103554T>G
LRG_135p1:p.Ile2179Met
NC_000011.9:g.108192112T>G
NM_000051.3:c.6537T>G
p.I2179M

Protein change:

I2179M

Links:

dbSNP: rs146243469

NCBI 1000 Genomes Browser:

rs146243469

Molecular consequence:

NM_001330368.2:c.641-12314A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.*39-12314A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000051.4:c.6537T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.6537T>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
SCV000292476	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Mar 13, 2024)	germline	clinical testing	Citation Link,
SCV000706961	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Uncertain significance (Mar 31, 2017)	germline	clinical testing	Citation Link,
SCV004222044	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Jun 19, 2023)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 25186627, 35264596, 23555315, 28093192, 35980532, 26467025
SCV004229297	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Uncertain significance (Jun 19, 2023)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 25186627, 35264596, 23555315, 28093192, 35980532, 26467025

Help

Summary from all submissions

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

Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel.

Tung N, Battelli C, Allen B, Kaldate R, Bhatnagar S, Bowles K, Timms K, Garber JE, Herold C, Ellisen L, Krejdovsky J, DeLeonardis K, Sedgwick K, Soltis K, Roa B, Wenstrup RJ, Hartman AR.

Cancer. 2015 Jan 1;121(1):25-33. doi: 10.1002/cncr.29010. Epub 2014 Sep 3.

PubMed [citation]

PMID:: 25186627

Detection of germline variants in Brazilian breast cancer patients using multigene panel testing.

Guindalini RSC, Viana DV, Kitajima JPFW, Rocha VM, López RVM, Zheng Y, Freitas É, Monteiro FPM, Valim A, Schlesinger D, Kok F, Olopade OI, Folgueira MAAK.

Sci Rep. 2022 Mar 9;12(1):4190. doi: 10.1038/s41598-022-07383-1.

PubMed [citation]

PMID:: 35264596
PMCID:: PMC8907244

See all PubMed Citations (6)

Details of each submission

From GeneDx, SCV000292476.16

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

Description

In silico analysis supports that this missense variant does not alter protein structure/function; Reported in a breast/prostate cancer case-control study, with no significant difference in frequency between cases and controls (p=0.28) (PMID: 23555315); Observed in individuals with a personal and/or family history of breast cancer, as well as an individual with pheochromocytoma/paraganglioma (PMID: 25186627, 31206626, 35264596, 35980532, 36568162, 37529773); This variant is associated with the following publications: (PMID: 28093192, 25186627, 32832836, 23532176, 31206626, 35264596, 35980532, 37529773, 23555315, 36568162)

#	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), SCV000706961.2

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV004222044.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

The frequency of this variant in the general population, 0.00056 (14/24972 chromosomes in African/African American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with breast cancer (PMIDs: 23555315 (2013), 25186627 (2015), and 35264596 (2022)). 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 benign or damaging. 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

From Athena Diagnostics, SCV004229297.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools disagree on the variant's effect on normal protein function.

#	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 24, 2024

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