NM_000051.4(ATM):c.5373T>C (p.Asp1791=) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jan 14, 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:: RCV001693497.5

Allele description [Variation Report for NM_000051.4(ATM):c.5373T>C (p.Asp1791=)]

NM_000051.4(ATM):c.5373T>C (p.Asp1791=)

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.5373T>C (p.Asp1791=)

HGVS:

NC_000011.10:g.108302906T>C
NG_009830.1:g.85075T>C
NM_000051.4:c.5373T>CMANE SELECT
NM_001351834.2:c.5373T>C
NP_000042.3:p.Asp1791=
NP_001338763.1:p.Asp1791=
LRG_135t1:c.5373T>C
LRG_135:g.85075T>C
NC_000011.9:g.108173633T>C
NM_000051.3:c.5373T>C

Links:

dbSNP: rs2135928197

NCBI 1000 Genomes Browser:

rs2135928197

Molecular consequence:

NM_000051.4:c.5373T>C - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001351834.2:c.5373T>C - synonymous variant - [Sequence Ontology: SO:0001819]

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001911467	Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	criteria provided, single submitter (Feliubadaló L et al. (Clin Chem 2021))	Uncertain significance (Jun 17, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003868795	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely benign (Jan 14, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001911467

Spanish ATM Cancer Susceptibility Variant Interpretation Working Group

criteria provided, single submitter

(Feliubadaló L et al. (Clin Chem 2021))

Uncertain significance
(Jun 17, 2020)

germline

clinical testing

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

SCV003868795

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely benign
(Jan 14, 2023)

germline

clinical testing

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
European caucasoid	germline	yes	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

A Collaborative Effort to Define Classification Criteria for ATM Variants in Hereditary Cancer Patients.

Feliubadaló L, Moles-Fernández A, Santamariña-Pena M, Sánchez AT, López-Novo A, Porras LM, Blanco A, Capellá G, de la Hoya M, Molina IJ, Osorio A, Pineda M, Rueda D, de la Cruz X, Diez O, Ruiz-Ponte C, Gutiérrez-Enríquez S, Vega A, Lázaro C.

Clin Chem. 2021 Mar 1;67(3):518-533. doi: 10.1093/clinchem/hvaa250.

PubMed [citation]

PMID:: 33280026

Details of each submission

From Spanish ATM Cancer Susceptibility Variant Interpretation Working Group, SCV001911467.1

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

Description

The c.5373T>C (p.Asp1791=) variant is absent from the gnomAD v2.1.1 non-cancer dataset, in a position with adequate coverage (>20x) (PM2; http://gnomad.broadinstitute.org). It is a silent variant not predicted to lead to a splicing alteration as per SPiCE predictor and no splicing site is created/activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice – GeneSplicer (BP4). The variant is located at a nucleotide that is not highly conserved across species, based on PhyloP (BP7). Therefore, this variant meets criteria to be classified as likely benign. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PM2 + BP4 + BP7 (PMID: 33280026).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Ambry Genetics, SCV003868795.2

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

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

Last Updated: Sep 8, 2024

ClinVar

Relating variation to medicine