NM_000059.3(BRCA2):c.5153A>G (p.Asn1718Ser) AND not provided

Clinical significance:Uncertain significance (Last evaluated: Feb 23, 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:
RCV000486901.3

Allele description [Variation Report for NM_000059.3(BRCA2):c.5153A>G (p.Asn1718Ser)]

NM_000059.3(BRCA2):c.5153A>G (p.Asn1718Ser)

Gene:
BRCA2:BRCA2 DNA repair associated [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
13q13.1
Genomic location:
Preferred name:
NM_000059.3(BRCA2):c.5153A>G (p.Asn1718Ser)
HGVS:
  • NC_000013.11:g.32339508A>G
  • NG_012772.3:g.29029A>G
  • NM_000059.3:c.5153A>G
  • NP_000050.2:p.Asn1718Ser
  • LRG_293t1:c.5153A>G
  • LRG_293:g.29029A>G
  • LRG_293p1:p.Asn1718Ser
  • NC_000013.10:g.32913645A>G
  • U43746.1:n.5381A>G
Protein change:
N1718S
Links:
dbSNP: rs80358739
NCBI 1000 Genomes Browser:
rs80358739
Molecular consequence:
  • NM_000059.3:c.5153A>G - 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
SCV000566491GeneDxcriteria provided, single submitter
Uncertain significance
(Feb 23, 2018)
germlineclinical testing

Citation Link,

SCV001469686Quest Diagnostics Nichols Institute San Juan Capistranocriteria provided, single submitter
Uncertain significance
(Feb 23, 2020)
unknownclinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV001549528Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria providedUncertain significanceunknownclinical testing

Summary from all submissions

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

Citations

PubMed

Benchmarking mutation effect prediction algorithms using functionally validated cancer-related missense mutations.

Martelotto LG, Ng CK, De Filippo MR, Zhang Y, Piscuoglio S, Lim RS, Shen R, Norton L, Reis-Filho JS, Weigelt B.

Genome Biol. 2014 Oct 28;15(10):484. doi: 10.1186/s13059-014-0484-1.

PubMed [citation]
PMID:
25348012
PMCID:
PMC4232638

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

Details of each submission

From GeneDx, SCV000566491.5

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

Description

This variant is denoted BRCA2 c.5153A>G at the cDNA level, p.Asn1718Ser (N1718S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). Using alternate nomenclature, this variant would be defined as BRCA2 5381A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Asn1718Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the RAD51 and POLH binding domains (Roy 2012, Buisson 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Asn1718Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001469686.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001549528.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided

Description

The BRCA2 p.Asn1718Ser variant was not identified in the literature nor was it identified in the LOVD 3.0 database. The variant was identified in dbSNP (ID: rs80358739) as "With Uncertain significance allele", ClinVar (classified as likely benign by Ambry Genetics; and as uncertain significance by GeneDx, Counsyl and BIC), and in UMD-LSDB (1x as unclassified variant). The variant was identified in control databases in 1 of 223044 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the Latino population in 1 of 27662 chromosomes (freq: 0.00004), while the variant was not observed in the African, Other, European, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Asn1718 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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

Last Updated: Apr 18, 2021

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