NM_000059.4(BRCA2):c.9227G>A (p.Gly3076Glu) AND none provided

Clinical significance:Likely pathogenic (Last evaluated: Oct 2, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001286967.1

Allele description [Variation Report for NM_000059.4(BRCA2):c.9227G>A (p.Gly3076Glu)]

NM_000059.4(BRCA2):c.9227G>A (p.Gly3076Glu)

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.9227G>A (p.Gly3076Glu)
HGVS:
  • NC_000013.11:g.32380116G>A
  • NG_012772.3:g.69637G>A
  • NM_000059.3:c.9227G>A
  • NM_000059.4:c.9227G>AMANE SELECT
  • NP_000050.2:p.Gly3076Glu
  • NP_000050.3:p.Gly3076Glu
  • LRG_293t1:c.9227G>A
  • LRG_293:g.69637G>A
  • LRG_293p1:p.Gly3076Glu
  • NC_000013.10:g.32954253G>A
  • NC_000013.10:g.32954253G>A
  • U43746.1:n.9455G>A
Protein change:
G3076E
Links:
dbSNP: rs80359187
NCBI 1000 Genomes Browser:
rs80359187
Molecular consequence:
  • NM_000059.3:c.9227G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000059.4:c.9227G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
none provided
Identifiers:
MedGen: CN235283

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001473600ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratoriescriteria provided, single submitter
Likely pathogenic
(Oct 2, 2019)
germlineclinical testing

Citation Link

Summary from all submissions

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

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories, SCV001473600.1

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

Description

The BRCA2 c.9227G>A; p.Gly3076Glu variant (rs80359187) is reported in the literature in multiple individuals with a personal and/or family history of breast, ovarian, and/or pancreatic cancer (Alemar 2017, Hahn 2003, Ikeda 2001, Li 2018). In one family, this variant segregated with disease in at least three affected family members (Hahn 2003). This variant is found on a single chromosome in the Genome Aggregation Database (1/250980 alleles), indicating it is not a common polymorphism. The glycine at codon 3076 is highly conserved, and functional analyses indicate decreased activity in assays of homology-directed recombination (HDR) (Guidugli 2013, Guidugli 2018). Additionally, other amino acid substitutions at this codon (p.Gly3076Arg, p.Gly3076Val) exhibit decreased HDR activity (Guidugli 2018), and p.Gly3076Val has been reported in a cohort of individuals with breast and/or ovarian cancer (Alemar 2017); however, the clinical significance of other variants at the same codon has not been conclusively determined. Still, based on available information, the p.Gly3076Glu variant is considered to be likely pathogenic. References: Alemar B et al. BRCA1 and BRCA2 mutational profile and prevalence in hereditary breast and ovarian cancer (HBOC) probands from Southern Brazil: Are international testing criteria appropriate for this specific population? PLoS One. 2017 Nov 21;12(11):e0187630. Guidugli L et al. A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity. Cancer Res. 2013 Jan 1;73(1):265-75. Guidugli L et al. Assessment of the Clinical Relevance of BRCA2 Missense Variants by Functional and Computational Approaches. Am J Hum Genet. 2018 Feb 1;102(2):233-248. Hahn SA et al. BRCA2 germline mutations in familial pancreatic carcinoma. J Natl Cancer Inst. 2003 Feb 5;95(3):214-21. Ikeda N et al. Frequency of BRCA1 and BRCA2 germline mutations in Japanese breast cancer families. Int J Cancer. 2001 Jan 1;91(1):83-8. Li A et al. BRCA germline mutations in an unselected nationwide cohort of Chinese patients with ovarian cancer and healthy controls. Gynecol Oncol. 2018 Oct;151(1):145-152.

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

Last Updated: Oct 25, 2021

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