NM_000051.4(ATM):c.3964C>A (p.Leu1322Ile) AND Hereditary cancer-predisposing syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Nov 7, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000132364.7

Allele description [Variation Report for NM_000051.4(ATM):c.3964C>A (p.Leu1322Ile)]

NM_000051.4(ATM):c.3964C>A (p.Leu1322Ile)

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.3964C>A (p.Leu1322Ile)
HGVS:
  • NC_000011.10:g.108284444C>A
  • NG_009830.1:g.66613C>A
  • NM_000051.3:c.3964C>A
  • NM_000051.4:c.3964C>AMANE SELECT
  • NM_001351834.2:c.3964C>A
  • NP_000042.3:p.Leu1322Ile
  • NP_000042.3:p.Leu1322Ile
  • NP_001338763.1:p.Leu1322Ile
  • LRG_135t1:c.3964C>A
  • LRG_135:g.66613C>A
  • LRG_135p1:p.Leu1322Ile
  • NC_000011.9:g.108155171C>A
  • p.L1322I
Protein change:
L1322I
Links:
dbSNP: rs144535256
NCBI 1000 Genomes Browser:
rs144535256
Molecular consequence:
  • NM_000051.3:c.3964C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000051.4:c.3964C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001351834.2:c.3964C>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

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
SCV000187454Ambry Geneticscriteria provided, single submitter
Likely benign
(Feb 28, 2018)
germlineclinical testing

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

Citation Link,

SCV000906587Color Health, Inccriteria provided, single submitter
Uncertain significance
(Nov 7, 2019)
germlineclinical testing

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

Description

This missense variant replaces leucine with isoleucine at codon 1322 of the ATM protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies showed that this variant had normal protein levels of ATM, activated ATM (ATM Ser-1981) and kinase activity (PMID:19431188). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 8/282554 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.

SCV000906587

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Citations

PubMed

Modeling ATM mutant proteins from missense changes confirms retained kinase activity.

Barone G, Groom A, Reiman A, Srinivasan V, Byrd PJ, Taylor AM.

Hum Mutat. 2009 Aug;30(8):1222-30. doi: 10.1002/humu.21034.

PubMed [citation]
PMID:
19431188

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, SCV000187454.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

Intact protein function observed in appropriate functional assay(s)

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

From Color Health, Inc, SCV000906587.2

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

Last Updated: Nov 27, 2021

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