NM_000051.4(ATM):c.5945A>G (p.Gln1982Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Oct 10, 2023
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:: RCV000130454.23

Allele description [Variation Report for NM_000051.4(ATM):c.5945A>G (p.Gln1982Arg)]

NM_000051.4(ATM):c.5945A>G (p.Gln1982Arg)

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.5945A>G (p.Gln1982Arg)

HGVS:

NC_000011.10:g.108312437A>G
NG_009830.1:g.94606A>G
NG_054724.1:g.162396T>C
NM_000051.4:c.5945A>GMANE SELECT
NM_001330368.2:c.641-3366T>C
NM_001351110.2:c.*39-3366T>C
NM_001351834.2:c.5945A>G
NP_000042.3:p.Gln1982Arg
NP_000042.3:p.Gln1982Arg
NP_001338763.1:p.Gln1982Arg
LRG_135t1:c.5945A>G
LRG_135:g.94606A>G
LRG_135p1:p.Gln1982Arg
NC_000011.9:g.108183164A>G
NM_000051.3:c.5945A>G
p.Q1982R

Protein change:

Q1982R

Links:

dbSNP: rs543980602

NCBI 1000 Genomes Browser:

rs543980602

Molecular consequence:

NM_001330368.2:c.641-3366T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.*39-3366T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000051.4:c.5945A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.5945A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000185319	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Sep 23, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000682291	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 10, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 12935933, 19781682, 32068069, 33471991, 25741868
SCV002537505	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Sep 18, 2021)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 25151137, 32068069, 33471991 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000185319

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Sep 23, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV000682291

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 10, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV002537505

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Sep 18, 2021)

germline

curation

PubMed (3)
[See all records that cite these PMIDs]

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, curation

Citations

PubMed

Absence of somatic ATM missense mutations in 58 mammary carcinomas.

Feng J, Yan J, Chen J, Schlake G, Jiang Z, Buzin CH, Sommer SS, Dritschilo A.

Cancer Genet Cytogenet. 2003 Sep;145(2):179-82.

PubMed [citation]

PMID:: 12935933

Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer.

Tavtigian SV, Oefner PJ, Babikyan D, Hartmann A, Healey S, Le Calvez-Kelm F, Lesueur F, Byrnes GB, Chuang SC, Forey N, Feuchtinger C, Gioia L, Hall J, Hashibe M, Herte B, McKay-Chopin S, Thomas A, Vallée MP, Voegele C, Webb PM, Whiteman DC; Australian Cancer Study.; et al.

Am J Hum Genet. 2009 Oct;85(4):427-46. doi: 10.1016/j.ajhg.2009.08.018. Epub 2009 Sep 24.

PubMed [citation]

PMID:: 19781682
PMCID:: PMC2756555

See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV000185319.8

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

Description

The p.Q1982R variant (also known as c.5945A>G), located in coding exon 39 of the ATM gene, results from an A to G substitution at nucleotide position 5945. The glutamine at codon 1982 is replaced by arginine, an amino acid with highly similar properties. This alteration has been detected in 0/4112 breast cancer patients and 1/2399 healthy control individuals across numerous studies (Tavtigian S et al. Am. J .Hum. Genet. 2009 Oct;85:427-46). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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 Color Diagnostics, LLC DBA Color Health, SCV000682291.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This missense variant replaces glutamine with arginine at codon 1982 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: cases: 12935933, 32068069, 33471991), and in unaffected controls (PMID: 19781682, 33471991). This variant has also been identified in 10/251190 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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 Sema4, Sema4, SCV002537505.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (3)

#	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 18, 2024

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