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NM_000051.4(ATM):c.3449G>C (p.Arg1150Thr) AND not specified

Clinical significance:Conflicting interpretations of pathogenicity, Uncertain significance(1); Likely benign(1) (Last evaluated: May 27, 2022)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV001818259.4

Allele description [Variation Report for NM_000051.4(ATM):c.3449G>C (p.Arg1150Thr)]

NM_000051.4(ATM):c.3449G>C (p.Arg1150Thr)

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.3449G>C (p.Arg1150Thr)
Other names:
p.R1150T:AGA>ACA
HGVS:
  • NC_000011.10:g.108281041G>C
  • NG_009830.1:g.63210G>C
  • NM_000051.4:c.3449G>CMANE SELECT
  • NM_001351834.2:c.3449G>C
  • NP_000042.3:p.Arg1150Thr
  • NP_000042.3:p.Arg1150Thr
  • NP_001338763.1:p.Arg1150Thr
  • LRG_135t1:c.3449G>C
  • LRG_135:g.63210G>C
  • LRG_135p1:p.Arg1150Thr
  • NC_000011.9:g.108151768G>C
  • NM_000051.3:c.3449G>C
Protein change:
R1150T
Links:
dbSNP: rs555219189
NCBI 1000 Genomes Browser:
rs555219189
Molecular consequence:
  • NM_000051.4:c.3449G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001351834.2:c.3449G>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
SCV002068402Genetic Services Laboratory,University of Chicagocriteria provided, single submitter
Uncertain significance
(Mar 2, 2018)
germlineclinical testing

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

SCV002548067Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely benign
(May 27, 2022)
germlineclinical testing

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

Citation Link

Summary from all submissions

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

Screening of over 1000 Indian patients with breast and/or ovarian cancer with a multi-gene panel: prevalence of BRCA1/2 and non-BRCA mutations.

Singh J, Thota N, Singh S, Padhi S, Mohan P, Deshwal S, Sur S, Ghosh M, Agarwal A, Sarin R, Ahmed R, Almel S, Chakraborti B, Raina V, DadiReddy PK, Smruti BK, Rajappa S, Dodagoudar C, Aggarwal S, Singhal M, Joshi A, Kumar R, et al.

Breast Cancer Res Treat. 2018 Jul;170(1):189-196. doi: 10.1007/s10549-018-4726-x. Epub 2018 Feb 22.

PubMed [citation]
PMID:
29470806

Details of each submission

From Genetic Services Laboratory,University of Chicago, SCV002068402.1

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002548067.1

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

Description

Variant summary: ATM c.3449G>C (p.Arg1150Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 251216 control chromosomes, predominantly at a frequency of 0.0015 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM (0.001) causing an ATM-related Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.3449G>C has been reported in the literature as a VUS in settings of multigene panel testing among individuals with a variety of cancers to include breast cancer (example, Singh_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia Telangiectasia/ATM-related cancers. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Likely benign, n=2; VUS, n=5). 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: Nov 29, 2022