NM_000051.4(ATM):c.6411C>G (p.Asp2137Glu) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Aug 3, 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:: RCV000221609.19

Allele description [Variation Report for NM_000051.4(ATM):c.6411C>G (p.Asp2137Glu)]

NM_000051.4(ATM):c.6411C>G (p.Asp2137Glu)

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.6411C>G (p.Asp2137Glu)

HGVS:

NC_000011.10:g.108320017C>G
NG_009830.1:g.102186C>G
NG_054724.1:g.154816G>C
NM_000051.4:c.6411C>GMANE SELECT
NM_001330368.2:c.641-10946G>C
NM_001351110.2:c.*39-10946G>C
NM_001351834.2:c.6411C>G
NP_000042.3:p.Asp2137Glu
NP_000042.3:p.Asp2137Glu
NP_001338763.1:p.Asp2137Glu
LRG_135t1:c.6411C>G
LRG_135:g.102186C>G
LRG_135p1:p.Asp2137Glu
NC_000011.9:g.108190744C>G
NM_000051.3:c.6411C>G

Protein change:

D2137E

Links:

dbSNP: rs780299607

NCBI 1000 Genomes Browser:

rs780299607

Molecular consequence:

NM_001330368.2:c.641-10946G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001351110.2:c.*39-10946G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000051.4:c.6411C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001351834.2:c.6411C>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

Recent activity

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DNAJB12 DnaJ heat shock protein family (Hsp40) member B12 [Homo sapiens]
DNAJB12 DnaJ heat shock protein family (Hsp40) member B12 [Homo sapiens]
Gene ID:54788

Gene
Gene Links for GEO Profiles (Select 119498663) (1)
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000278080	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Aug 3, 2023)	germline	clinical testing	Citation Link,
SCV000682333	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 25, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002537322	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Apr 20, 2021)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000278080

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Aug 3, 2023)

germline

clinical testing

Citation Link,

SCV000682333

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jul 25, 2023)

germline

clinical testing

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

SCV002537322

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Apr 20, 2021)

germline

curation

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

Details of each submission

From Ambry Genetics, SCV000278080.8

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

Description

The p.D2137E variant (also known as c.6411C>G), located in coding exon 43 of the ATM gene, results from a C to G substitution at nucleotide position 6411. The aspartic acid at codon 2137 is replaced by glutamic acid, 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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV000682333.4

#	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 aspartic acid with glutamic acid at codon 2137 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 not been reported in individuals affected with ATM-related disorders in the literature. This variant has been identified in 2/280996 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, SCV002537322.1

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

Last Updated: Nov 3, 2024

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