NM_000051.4(ATM):c.4853G>A (p.Arg1618Gln) AND Hereditary cancer-predisposing syndrome

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

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Feb 14, 2022
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:: RCV000164315.8

Allele description

NM_000051.4(ATM):c.4853G>A (p.Arg1618Gln)

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.4853G>A (p.Arg1618Gln)

HGVS:

NC_000011.10:g.108295003G>A
NG_009830.1:g.77172G>A
NM_000051.4:c.4853G>AMANE SELECT
NM_001351834.2:c.4853G>A
NP_000042.3:p.Arg1618Gln
NP_000042.3:p.Arg1618Gln
NP_001338763.1:p.Arg1618Gln
LRG_135t1:c.4853G>A
LRG_135:g.77172G>A
LRG_135p1:p.Arg1618Gln
NC_000011.9:g.108165730G>A
NM_000051.3:c.4853G>A
p.R1618Q

Protein change:

R1618Q

Links:

dbSNP: rs765759912

NCBI 1000 Genomes Browser:

rs765759912

Molecular consequence:

NM_000051.4:c.4853G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.4853G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000214946	Ambry Genetics	criteria provided, single submitter (Ambry Autosomal Dominant and X-Linked criteria (7/2020))	Uncertain significance (Aug 25, 2020)	germline	clinical testing	Citation Link,
SCV000903054	Color Health, Inc	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 12, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002535432	Sema4,Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Feb 14, 2022)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 30303537, 34359559 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000214946

Ambry Genetics

criteria provided, single submitter

(Ambry Autosomal Dominant and X-Linked criteria (7/2020))

Uncertain significance
(Aug 25, 2020)

germline

clinical testing

Citation Link,

SCV000903054

Color Health, Inc

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 12, 2021)

germline

clinical testing

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

SCV002535432

Sema4,Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Feb 14, 2022)

germline

curation

PubMed (2)
[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	1	not provided	not provided	1	not provided	clinical testing, curation

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

Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing.

Girard E, Eon-Marchais S, Olaso R, Renault AL, Damiola F, Dondon MG, Barjhoux L, Goidin D, Meyer V, Le Gal D, Beauvallet J, Mebirouk N, Lonjou C, Coignard J, Marcou M, Cavaciuti E, Baulard C, Bihoreau MT, Cohen-Haguenauer O, Leroux D, Penet C, Fert-Ferrer S, et al.

Int J Cancer. 2019 Apr 15;144(8):1962-1974. doi: 10.1002/ijc.31921. Epub 2018 Nov 13.

PubMed [citation]

PMID:: 30303537
PMCID:: PMC6587727

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000214946.6

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

Description

The p.R1618Q variant (also known as c.4853G>A), located in coding exon 31 of the ATM gene, results from a G to A substitution at nucleotide position 4853. The arginine at codon 1618 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is well 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	1	not provided	not provided		1	not provided	not provided	not provided

From Color Health, Inc, SCV000903054.2

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

Description

This missense variant replaces arginine with glutamine at codon 1618 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: 30303537). This variant has been identified in 12/251334 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, SCV002535432.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (2)

#	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: Aug 23, 2022

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