NM_000059.3(BRCA2):c.10024G>A (p.Glu3342Lys) AND not specified

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

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000445222.2

Allele description [Variation Report for NM_000059.3(BRCA2):c.10024G>A (p.Glu3342Lys)]

NM_000059.3(BRCA2):c.10024G>A (p.Glu3342Lys)

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.10024G>A (p.Glu3342Lys)
HGVS:
  • NC_000013.11:g.32398537G>A
  • NG_012772.3:g.88058G>A
  • NM_000059.3:c.10024G>A
  • NP_000050.2:p.Glu3342Lys
  • LRG_293t1:c.10024G>A
  • LRG_293:g.88058G>A
  • LRG_293p1:p.Glu3342Lys
  • NC_000013.10:g.32972674G>A
Nucleotide change:
10252G>A
Protein change:
E3342K
Links:
dbSNP: rs28897761
NCBI 1000 Genomes Browser:
rs28897761
Molecular consequence:
  • NM_000059.3:c.10024G>A - 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
SCV000526510GeneDxcriteria provided, single submitter
Likely benign
(Dec 13, 2016)
germlineclinical testing

Citation Link,

SCV000694487Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Uncertain significance
(Jul 1, 2019)
germlineclinical testing

PubMed (4)
[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

BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group.

Alsop K, Fereday S, Meldrum C, deFazio A, Emmanuel C, George J, Dobrovic A, Birrer MJ, Webb PM, Stewart C, Friedlander M, Fox S, Bowtell D, Mitchell G.

J Clin Oncol. 2012 Jul 20;30(21):2654-63. doi: 10.1200/JCO.2011.39.8545. Epub 2012 Jun 18. Erratum in: J Clin Oncol. 2012 Nov 20;30(33):4180.

PubMed [citation]
PMID:
22711857
PMCID:
PMC3413277

Mutational landscape of gastric adenocarcinoma in Chinese: implications for prognosis and therapy.

Chen K, Yang D, Li X, Sun B, Song F, Cao W, Brat DJ, Gao Z, Li H, Liang H, Zhao Y, Zheng H, Li M, Buckner J, Patterson SD, Ye X, Reinhard C, Bhathena A, Joshi D, Mischel PS, Croce CM, Wang YM, et al.

Proc Natl Acad Sci U S A. 2015 Jan 27;112(4):1107-12. doi: 10.1073/pnas.1422640112. Epub 2015 Jan 12.

PubMed [citation]
PMID:
25583476
PMCID:
PMC4313862
See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000526510.4

#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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000694487.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

Variant summary: BRCA2 c.10024G>A (p.Glu3342Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250966 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.10024G>A, has been reported in the literature in individuals affected with breast and/or ovarian cancer (Alsop_2012, Azzollini_2016). However, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. One publication reports that this variant was found to co-occur with a pathogenic change but do specify the pathogenic variant (Alsop_2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four other submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (2x uncertain significance and 2x benign). Based on the evidence outlined above, the variant was classified as uncertain significance until additional information becomes available.

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

Last Updated: Jun 14, 2021

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