NM_002485.5(NBN):c.758C>T (p.Thr253Ile) AND not specified

Clinical significance:Likely benign (Last evaluated: Oct 22, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000121624.5

Allele description [Variation Report for NM_002485.5(NBN):c.758C>T (p.Thr253Ile)]

NM_002485.5(NBN):c.758C>T (p.Thr253Ile)

Gene:
NBN:nibrin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
8q21.3
Genomic location:
Preferred name:
NM_002485.5(NBN):c.758C>T (p.Thr253Ile)
Other names:
p.T253I:ACA>ATA
HGVS:
  • NC_000008.11:g.89970502G>A
  • NG_008860.1:g.19170C>T
  • NM_001024688.3:c.512C>T
  • NM_002485.4:c.758C>T
  • NM_002485.5:c.758C>TMANE SELECT
  • NP_001019859.1:p.Thr171Ile
  • NP_002476.2:p.Thr253Ile
  • NP_002476.2:p.Thr253Ile
  • LRG_158t1:c.758C>T
  • LRG_158:g.19170C>T
  • LRG_158p1:p.Thr253Ile
  • NC_000008.10:g.90982730G>A
  • p.T253I
Protein change:
T171I
Links:
dbSNP: rs61754967
NCBI 1000 Genomes Browser:
rs61754967
Molecular consequence:
  • NM_001024688.3:c.512C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002485.4:c.758C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002485.5:c.758C>T - 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
SCV000085822ITMIno assertion providednot providedgermlinereference population

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

SCV000601701Quest Diagnostics Nichols Institute San Juan Capistranocriteria provided, single submitter
Likely benign
(Jul 6, 2017)
germlineclinical testing

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

SCV000917861Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely benign
(Oct 22, 2020)
germlineclinical testing

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

Citation Link

Description

Please see associated publication for description of ethnicities

SCV000085822

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
Africangermlineunknownnot providednot providednot provided43not providedreference population
African_Europeangermlineunknownnot providednot providednot provided46not providedreference population
Central_Asiangermlineunknownnot providednot providednot provided50not providedreference population
East_Asiangermlineunknownnot providednot providednot provided62not providedreference population
Europeangermlineunknownnot providednot providednot provided331not providedreference population
Hispanicgermlineunknownnot providednot providednot provided118not providedreference population
Whole_cohortgermlineunknownnot providednot providednot provided681not providedreference population

Citations

PubMed

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]
PMID:
26467025
PMCID:
PMC4737317

Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing.

Bodian DL, McCutcheon JN, Kothiyal P, Huddleston KC, Iyer RK, Vockley JG, Niederhuber JE.

PLoS One. 2014;9(4):e94554. doi: 10.1371/journal.pone.0094554.

PubMed [citation]
PMID:
24728327
PMCID:
PMC3984285
See all PubMed Citations (4)

Details of each submission

From ITMI, SCV000085822.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1Africannot providednot providednot providedreference population PubMed (1)
2African_Europeannot providednot providednot providedreference population PubMed (1)
3Central_Asiannot providednot providednot providedreference population PubMed (1)
4East_Asiannot providednot providednot providedreference population PubMed (1)
5Europeannot providednot providednot providedreference population PubMed (1)
6Hispanicnot providednot providednot providedreference population PubMed (1)
7Whole_cohortnot providednot providednot providedreference population PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown43not provideddiscoverynot provided0not providednot provided
2germlineunknown46not provideddiscoverynot provided0not providednot provided
3germlineunknown50not provideddiscoverynot provided0.03not providednot provided
4germlineunknown62not provideddiscoverynot provided0not providednot provided
5germlineunknown331not provideddiscoverynot provided0not providednot provided
6germlineunknown118not provideddiscoverynot provided0not providednot provided
7germlineunknown681not provideddiscoverynot provided0.0022not providednot provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000601701.1

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000917861.2

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

Description

Variant summary: NBN c.758C>T (p.Thr253Ile) results in a non-conservative amino acid change located in the Nibrin, second BRCT domain of 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 0.00041 in 251260 control chromosomes, predominantly at a frequency of 0.0032 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 1.3- fold the estimated maximal expected allele frequency for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome phenotype (0.0025), suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.758C>T has been reported in the literature in healthy individuals (e.g. Bodian_2014) and at least one cancer cell line (e.g. Sun_2018). These reports do not provide unequivocal conclusions about association of the variant with Nijmegen Breakage Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as benign/ likely benign (n=4) and uncertain significance (n=2). 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 27, 2021

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