NM_000051.4(ATM):c.2476A>C (p.Ile826Leu) AND not specified

Clinical significance:Uncertain significance (Last evaluated: Aug 13, 2021)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000779790.2

Allele description [Variation Report for NM_000051.4(ATM):c.2476A>C (p.Ile826Leu)]

NM_000051.4(ATM):c.2476A>C (p.Ile826Leu)

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.2476A>C (p.Ile826Leu)
HGVS:
  • NC_000011.10:g.108267180A>C
  • NG_009830.1:g.49349A>C
  • NM_000051.4:c.2476A>CMANE SELECT
  • NM_001351834.2:c.2476A>C
  • NP_000042.3:p.Ile826Leu
  • NP_000042.3:p.Ile826Leu
  • NP_001338763.1:p.Ile826Leu
  • LRG_135t1:c.2476A>C
  • LRG_135:g.49349A>C
  • LRG_135p1:p.Ile826Leu
  • NC_000011.9:g.108137907A>C
  • NM_000051.3:c.2476A>C
  • p.I826L
Protein change:
I826L
Links:
dbSNP: rs587782397
NCBI 1000 Genomes Browser:
rs587782397
Molecular consequence:
  • NM_000051.4:c.2476A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001351834.2:c.2476A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000916592Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Uncertain significance
(Aug 13, 2021)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

ATM germline mutations in women with familial breast cancer and a relative with haematological malignancy.

Paglia LL, Laugé A, Weber J, Champ J, Cavaciuti E, Russo A, Viovy JL, Stoppa-Lyonnet D.

Breast Cancer Res Treat. 2010 Jan;119(2):443-52. doi: 10.1007/s10549-009-0396-z. Epub 2009 Apr 29.

PubMed [citation]
PMID:
19404735

Radiation exposure, the ATM Gene, and contralateral breast cancer in the women's environmental cancer and radiation epidemiology study.

Bernstein JL, Haile RW, Stovall M, Boice JD Jr, Shore RE, Langholz B, Thomas DC, Bernstein L, Lynch CF, Olsen JH, Malone KE, Mellemkjaer L, Borresen-Dale AL, Rosenstein BS, Teraoka SN, Diep AT, Smith SA, Capanu M, Reiner AS, Liang X, Gatti RA, Concannon P; et al.

J Natl Cancer Inst. 2010 Apr 7;102(7):475-83. doi: 10.1093/jnci/djq055. Epub 2010 Mar 19.

PubMed [citation]
PMID:
20305132
PMCID:
PMC2902825
See all PubMed Citations (4)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000916592.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

Variant summary: ATM c.2476A>C (p.Ile826Leu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251692 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (4e-05 vs 0.004), allowing no conclusion about variant significance. The variant, c.2476A>C, has been reported in the literature in individuals affected with Breast Cancer (Bernstein_2010) and CLL (Guarini_2012, LaPaglia_2009, Tiao_2017). These reports however, do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=6) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Dec 4, 2021

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