NM_000059.4(BRCA2):c.9986A>G (p.Asn3329Ser) AND not specified

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(2);Uncertain significance(1) (Last evaluated: Dec 26, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000425781.2

Allele description [Variation Report for NM_000059.4(BRCA2):c.9986A>G (p.Asn3329Ser)]

NM_000059.4(BRCA2):c.9986A>G (p.Asn3329Ser)

Gene:
BRCA2:BRCA2 DNA repair associated [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
13q13.1
Genomic location:
Preferred name:
NM_000059.4(BRCA2):c.9986A>G (p.Asn3329Ser)
HGVS:
  • NC_000013.11:g.32398499A>G
  • NG_012772.3:g.88020A>G
  • NM_000059.3:c.9986A>G
  • NM_000059.4:c.9986A>GMANE SELECT
  • NP_000050.2:p.Asn3329Ser
  • NP_000050.3:p.Asn3329Ser
  • LRG_293t1:c.9986A>G
  • LRG_293:g.88020A>G
  • LRG_293p1:p.Asn3329Ser
  • NC_000013.10:g.32972636A>G
  • p.N3329S
Protein change:
N3329S
Links:
dbSNP: rs76635144
NCBI 1000 Genomes Browser:
rs76635144
Molecular consequence:
  • NM_000059.3:c.9986A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000059.4:c.9986A>G - 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
SCV000518147GeneDxcriteria provided, single submitter
Likely benign
(May 26, 2016)
germlineclinical testing

Citation Link,

SCV000600886Quest Diagnostics Nichols Institute San Juan Capistranocriteria provided, single submitter
Uncertain significance
(Nov 23, 2016)
germlineclinical testing

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

SCV001361748Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely benign
(Dec 26, 2019)
germlineclinical testing

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

Citation Link

Summary from all submissions

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

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

BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients.

Kote-Jarai Z, Leongamornlert D, Saunders E, Tymrakiewicz M, Castro E, Mahmud N, Guy M, Edwards S, O'Brien L, Sawyer E, Hall A, Wilkinson R, Dadaev T, Goh C, Easton D; UKGPCS Collaborators., Goldgar D, Eeles R.

Br J Cancer. 2011 Oct 11;105(8):1230-4. doi: 10.1038/bjc.2011.383. Epub 2011 Sep 27.

PubMed [citation]
PMID:
21952622
PMCID:
PMC3208504
See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000518147.4

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

Description

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

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

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000600886.1

#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, SCV001361748.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Variant summary: BRCA2 c.9986A>G (p.Asn3329Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 250776 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. Furthermore, the variant has been observed in at-least one woman in a database of women who are cancer free and older than age 70 (FLOSSIES database). c.9986A>G has been reported in the literature in at-least one individual affected with Prostate cancer (Kote-Jarai_2011) and as a VUS in one family undergoing testing for the BRCA1/2 genes (Zuntini_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At-least one co-occurrence with another pathogenic variant has been reported at our laboratory (BRCA2 c.1755_1759delGAAAA, p.Lys585fsX3), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six 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=3; VUS, n=3) some of whom report overlapping evidence utilized in the context of this evaluation. In six years of tracking this variant at our laboratory, no convincing evidence supporting a pathogenic outcome has been ascertained and all emerging evidence seem to point towards a likely benign outcome. Based on the evidence outlined above, the variant was re-classified as likely benign.

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

Last Updated: Jun 14, 2021

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