NM_000051.4(ATM):c.3295G>A (p.Asp1099Asn) AND Hereditary cancer-predisposing syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Sep 25, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000214286.4

Allele description [Variation Report for NM_000051.4(ATM):c.3295G>A (p.Asp1099Asn)]

NM_000051.4(ATM):c.3295G>A (p.Asp1099Asn)

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.3295G>A (p.Asp1099Asn)
HGVS:
  • NC_000011.10:g.108279501G>A
  • NG_009830.1:g.61670G>A
  • NM_000051.3:c.3295G>A
  • NM_000051.4:c.3295G>AMANE SELECT
  • NM_001351834.2:c.3295G>A
  • NP_000042.3:p.Asp1099Asn
  • NP_000042.3:p.Asp1099Asn
  • NP_001338763.1:p.Asp1099Asn
  • LRG_135t1:c.3295G>A
  • LRG_135:g.61670G>A
  • LRG_135p1:p.Asp1099Asn
  • NC_000011.9:g.108150228G>A
Protein change:
D1099N
Links:
dbSNP: rs372966951
NCBI 1000 Genomes Browser:
rs372966951
Molecular consequence:
  • NM_000051.3:c.3295G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000051.4:c.3295G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001351834.2:c.3295G>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
SCV000278510Ambry Geneticscriteria provided, single submitter
Uncertain significance
(Sep 25, 2020)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV000910978Color Health, Inccriteria provided, single submitter
Likely benign
(Oct 31, 2016)
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

Citations

PubMed

Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer.

Tavtigian SV, Oefner PJ, Babikyan D, Hartmann A, Healey S, Le Calvez-Kelm F, Lesueur F, Byrnes GB, Chuang SC, Forey N, Feuchtinger C, Gioia L, Hall J, Hashibe M, Herte B, McKay-Chopin S, Thomas A, Vallée MP, Voegele C, Webb PM, Whiteman DC; Australian Cancer Study.; et al.

Am J Hum Genet. 2009 Oct;85(4):427-46. doi: 10.1016/j.ajhg.2009.08.018. Epub 2009 Sep 24.

PubMed [citation]
PMID:
19781682
PMCID:
PMC2756555

Multigene testing of moderate-risk genes: be mindful of the missense.

Young EL, Feng BJ, Stark AW, Damiola F, Durand G, Forey N, Francy TC, Gammon A, Kohlmann WK, Kaphingst KA, McKay-Chopin S, Nguyen-Dumont T, Oliver J, Paquette AM, Pertesi M, Robinot N, Rosenthal JS, Vallee M, Voegele C, Hopper JL, Southey MC, Andrulis IL, et al.

J Med Genet. 2016 Jun;53(6):366-76. doi: 10.1136/jmedgenet-2015-103398. Epub 2016 Jan 19.

PubMed [citation]
PMID:
26787654
PMCID:
PMC4893078
See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000278510.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (3)

Description

The p.D1099N variant (also known as c.3295G>A), located in coding exon 22 of the ATM gene, results from a G to A substitution at nucleotide position 3295. The aspartic acid at codon 1099 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in multiple breast cancer patients (Tavtigian SV et al. Am. J. Hum. Genet., 2009 Oct;85:427-46; Young EL et al. J. Med. Genet., 2016 06;53:366-76; Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660). This amino acid position is not 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.

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

From Color Health, Inc, SCV000910978.1

#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: Oct 30, 2021

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