NM_000051.4(ATM):c.3919G>A (p.Gly1307Arg) AND not specified

Clinical significance:Likely benign (Last evaluated: Sep 14, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000608362.2

Allele description [Variation Report for NM_000051.4(ATM):c.3919G>A (p.Gly1307Arg)]

NM_000051.4(ATM):c.3919G>A (p.Gly1307Arg)

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.3919G>A (p.Gly1307Arg)
HGVS:
  • NC_000011.10:g.108284399G>A
  • NG_009830.1:g.66568G>A
  • NM_000051.4:c.3919G>AMANE SELECT
  • NM_001351834.2:c.3919G>A
  • NP_000042.3:p.Gly1307Arg
  • NP_000042.3:p.Gly1307Arg
  • NP_001338763.1:p.Gly1307Arg
  • LRG_135t1:c.3919G>A
  • LRG_135:g.66568G>A
  • LRG_135p1:p.Gly1307Arg
  • NC_000011.9:g.108155126G>A
  • NM_000051.3:c.3919G>A
  • p.G1307R
Protein change:
G1307R
Links:
dbSNP: rs568451087
NCBI 1000 Genomes Browser:
rs568451087
Molecular consequence:
  • NM_000051.4:c.3919G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001351834.2:c.3919G>A - 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
SCV001437333Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely benign
(Sep 14, 2020)
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

Patterns and functional implications of rare germline variants across 12 cancer types.

Lu C, Xie M, Wendl MC, Wang J, McLellan MD, Leiserson MD, Huang KL, Wyczalkowski MA, Jayasinghe R, Banerjee T, Ning J, Tripathi P, Zhang Q, Niu B, Ye K, Schmidt HK, Fulton RS, McMichael JF, Batra P, Kandoth C, Bharadwaj M, Koboldt DC, et al.

Nat Commun. 2015 Dec 22;6:10086. doi: 10.1038/ncomms10086.

PubMed [citation]
PMID:
26689913
PMCID:
PMC4703835

Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing.

Mandelker D, Zhang L, Kemel Y, Stadler ZK, Joseph V, Zehir A, Pradhan N, Arnold A, Walsh MF, Li Y, Balakrishnan AR, Syed A, Prasad M, Nafa K, Carlo MI, Cadoo KA, Sheehan M, Fleischut MH, Salo-Mullen E, Trottier M, Lipkin SM, Lincoln A, et al.

JAMA. 2017 Sep 5;318(9):825-835. doi: 10.1001/jama.2017.11137. Erratum in: JAMA. 2018 Dec 11;320(22):2381.

PubMed [citation]
PMID:
28873162
PMCID:
PMC5611881
See all PubMed Citations (4)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001437333.1

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

Description

Variant summary: ATM c.3919G>A (p.Gly1307Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00036 in 251256 control chromosomes, predominantly at a frequency of 0.0029 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.3919G>A has been reported in the literature in individuals affected with cancer including low grade glioma and breast cancer (e.g. Shayeghi_1998, Lu_2015, Mandelker_2017) but was also reported in non-cancer controls (e.g. Pritchard_2018). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. One submitter in LOVD reports co-occurrence of the variant with 2 undefined pathogenic variants and classifies it as benign. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and one ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.

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

Last Updated: Dec 4, 2021

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