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

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

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000656925.5

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]
Observations:
1

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000149714GeneDxcriteria provided, single submitter
Likely benign
(Oct 22, 2020)
germlineclinical testing

Citation Link,

SCV001554413Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria providedLikely benignunknownclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownyes1not providednot providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From GeneDx, SCV000149714.12

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24728327, 31278556)

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

From Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001554413.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided

Description

The NBN p.Thr253Ile variant was identified in the literature from healthy individuals in 3 of 1362 control chromosomes (frequency: 0.002) (Bodian 2014). The variant was also identified in the following databases: dbSNP (ID: rs61754967) as "With Uncertain significance allele", ClinVar (2x uncertain significance, 2x likely benign), Clinvitae (2x uncertain significance, 1x likely benign), and the Zhejiang Colon Cancer Database. The variant was not identified in the Cosmic or LOVD 3.0 databases. The variant was identified in control databases in 100 of 276924 chromosomes (1 homozygous) at a frequency of 0.0004 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include Other in 1 of 6454 chromosomes (freq: 0.0002) and South Asian in 99 of 30782 chromosomes (freq: 0.003). The variant was not observed in the African, Latino, European, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Thr253 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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

Last Updated: Oct 30, 2021

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