NM_000051.4(ATM):c.2074C>T (p.Arg692Cys) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Feb 27, 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:: RCV000164063.14

Allele description [Variation Report for NM_000051.4(ATM):c.2074C>T (p.Arg692Cys)]

NM_000051.4(ATM):c.2074C>T (p.Arg692Cys)

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.2074C>T (p.Arg692Cys)

HGVS:

NC_000011.10:g.108253989C>T
NG_009830.1:g.36158C>T
NM_000051.4:c.2074C>TMANE SELECT
NM_001351834.2:c.2074C>T
NP_000042.3:p.Arg692Cys
NP_000042.3:p.Arg692Cys
NP_001338763.1:p.Arg692Cys
LRG_135t1:c.2074C>T
LRG_135:g.36158C>T
LRG_135p1:p.Arg692Cys
NC_000011.9:g.108124716C>T
NM_000051.3:c.2074C>T
p.R692C

Protein change:

R692C

Links:

dbSNP: rs765965513

NCBI 1000 Genomes Browser:

rs765965513

Molecular consequence:

NM_000051.4:c.2074C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.2074C>T - 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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Propionibacterium sp. JGI 0001020-A16
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000214673	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Aug 28, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000911566	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 27, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26898890, 28779002, 33471991, 25741868
SCV002534044	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Jun 11, 2021)	germline	curation	PubMed (4) [See all records that cite these PMIDs] 26898890, 28779002, 28652578, 33471991 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000214673

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Aug 28, 2018)

germline

clinical testing

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

Citation Link,

SCV000911566

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 27, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002534044

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Jun 11, 2021)

germline

curation

PubMed (4)
[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

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

Prioritizing Variants in Complete Hereditary Breast and Ovarian Cancer Genes in Patients Lacking Known BRCA Mutations.

Caminsky NG, Mucaki EJ, Perri AM, Lu R, Knoll JH, Rogan PK.

Hum Mutat. 2016 Jul;37(7):640-52. doi: 10.1002/humu.22972. Epub 2016 Mar 18.

PubMed [citation]

PMID:: 26898890

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000214673.7

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

Description

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

#	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, SCV000911566.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This missense variant replaces arginine with cysteine at codon 692 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: 26898890, 28779002). In a large international case-control study, this variant was absent in 60466 breast cancer cases and reported in 1/53460 controls (PMID: 33471991). This variant has been identified in 3/251328 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, SCV002534044.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (4)

#	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: Oct 13, 2024

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