NM_000051.4(ATM):c.4396C>G (p.Arg1466Gly) AND Hereditary cancer-predisposing syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(2) (Last evaluated: Jul 16, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000159723.9

Allele description [Variation Report for NM_000051.4(ATM):c.4396C>G (p.Arg1466Gly)]

NM_000051.4(ATM):c.4396C>G (p.Arg1466Gly)

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.4396C>G (p.Arg1466Gly)
Other names:
p.R1466G:CGA>GGA
HGVS:
  • NC_000011.10:g.108289761C>G
  • NG_009830.1:g.71930C>G
  • NM_000051.3:c.4396C>G
  • NM_000051.4:c.4396C>GMANE SELECT
  • NM_001351834.2:c.4396C>G
  • NP_000042.3:p.Arg1466Gly
  • NP_000042.3:p.Arg1466Gly
  • NP_001338763.1:p.Arg1466Gly
  • LRG_135t1:c.4396C>G
  • LRG_135:g.71930C>G
  • LRG_135p1:p.Arg1466Gly
  • NC_000011.9:g.108160488C>G
  • p.R1466G
Protein change:
R1466G
Links:
dbSNP: rs730881369
NCBI 1000 Genomes Browser:
rs730881369
Molecular consequence:
  • NM_000051.3:c.4396C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000051.4:c.4396C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001351834.2:c.4396C>G - missense variant - [Sequence Ontology: SO:0001583]
Observations:
5

Condition(s)

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000215787Ambry Geneticscriteria provided, single submitter
Likely benign
(Jul 16, 2020)
germlineclinical testing

Citation Link,

SCV000682202Color Health, Inccriteria provided, single submitter
Uncertain significance
(Mar 1, 2019)
germlineclinical testing

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

SCV001911461Spanish ATM Cancer Susceptibility Variant Interpretation Working Groupcriteria provided, single submitter
Uncertain significance
(Jun 17, 2020)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing
European caucasoidgermlineyes4not providednot provided4not providedclinical testing

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

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 Ambry Genetics, SCV000215787.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided

Description

Other strong data supporting benign classification

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

From Color Health, Inc, SCV000682202.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Spanish ATM Cancer Susceptibility Variant Interpretation Working Group, SCV001911461.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1European caucasoid1not providednot providedclinical testing PubMed (1)
2European caucasoid1not providednot providedclinical testing PubMed (1)
3European caucasoid1not providednot providedclinical testing PubMed (1)
4European caucasoid1not providednot providedclinical testing PubMed (1)

Description

The c.4396C>G (p.Arg1466Gly) variant appears only twice in the gnomAD v2.1.1 non-cancer dataset (0.0007% frequency), specifically in the European (non-Finnish) subpopulation (PM2; http://gnomad.broadinstitute.org). This missense variant is 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, but it alters the protein function / structure on the in-silico prediction reports of REVEL and VEST4 (PP3). There is no other supporting data that meet criteria for consideration. Therefore, the clinical significance of this variant is uncertain. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PM2 + PP3 (PMID: 33280026).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided
2germlineyes1not providednot provided1not providednot providednot provided
3germlineyes1not providednot provided1not providednot providednot provided
4germlineyes1not providednot provided1not providednot providednot provided

Last Updated: Oct 25, 2021

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