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NM_000059.4(BRCA2):c.3437A>G (p.Glu1146Gly) AND Hereditary cancer-predisposing syndrome

Germline classification:
Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:
Jun 9, 2023
Review status:
criteria provided, conflicting classifications
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000129732.23

Allele description [Variation Report for NM_000059.4(BRCA2):c.3437A>G (p.Glu1146Gly)]

NM_000059.4(BRCA2):c.3437A>G (p.Glu1146Gly)

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.3437A>G (p.Glu1146Gly)
HGVS:
  • NC_000013.11:g.32337792A>G
  • NG_012772.3:g.27313A>G
  • NM_000059.4:c.3437A>GMANE SELECT
  • NP_000050.2:p.Glu1146Gly
  • NP_000050.3:p.Glu1146Gly
  • LRG_293t1:c.3437A>G
  • LRG_293:g.27313A>G
  • LRG_293p1:p.Glu1146Gly
  • NC_000013.10:g.32911929A>G
  • NM_000059.3:c.3437A>G
  • U43746.1:n.3665A>G
  • p.E1146G
Nucleotide change:
3665A>G
Protein change:
E1146G
Links:
dbSNP: rs80358588
NCBI 1000 Genomes Browser:
rs80358588
Molecular consequence:
  • NM_000059.4:c.3437A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000184537Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)
Uncertain significance
(Jun 9, 2023)
germlineclinical testing

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

Citation Link,

SCV000821933GeneKor MSA
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Aug 1, 2018)
germlineclinical testing

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

SCV000906898Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Apr 11, 2023)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV003851960University of Washington Department of Laboratory Medicine, University of Washington
criteria provided, single submitter

(Dines et al. (Genet Med. 2020))
Likely benign
(Mar 23, 2023)
germlinecuration

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

Summary from all submissions

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

Citations

PubMed

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification.

Parsons MT, Tudini E, Li H, Hahnen E, Wappenschmidt B, Feliubadaló L, Aalfs CM, Agata S, Aittomäki K, Alducci E, Alonso-Cerezo MC, Arnold N, Auber B, Austin R, Azzollini J, Balmaña J, Barbieri E, Bartram CR, Blanco A, Blümcke B, Bonache S, Bonanni B, et al.

Hum Mutat. 2019 Sep;40(9):1557-1578. doi: 10.1002/humu.23818.

PubMed [citation]
PMID:
31131967
PMCID:
PMC6772163

Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations.

Tsaousis GN, Papadopoulou E, Apessos A, Agiannitopoulos K, Pepe G, Kampouri S, Diamantopoulos N, Floros T, Iosifidou R, Katopodi O, Koumarianou A, Markopoulos C, Papazisis K, Venizelos V, Xanthakis I, Xepapadakis G, Banu E, Eniu DT, Negru S, Stanculeanu DL, Ungureanu A, Ozmen V, et al.

BMC Cancer. 2019 Jun 3;19(1):535. doi: 10.1186/s12885-019-5756-4.

PubMed [citation]
PMID:
31159747
PMCID:
PMC6547505
See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV000184537.9

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

Description

The p.E1146G variant (also known as c.3437A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 3437. The glutamic acid at codon 1146 is replaced by glycine, an amino acid with similar properties. This alteration has been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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

From GeneKor MSA, SCV000821933.1

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

From Color Diagnostics, LLC DBA Color Health, SCV000906898.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This missense variant replaces glutamic acid with glycine at codon 1146 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual who underwent cancer genetic testing (PMID: 31159747) and is associated with a family history likelihood ratio for pathogenicity of 4.372 (PMID: 31131967). This variant has been identified in 1/251038 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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

From University of Washington Department of Laboratory Medicine, University of Washington, SCV003851960.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (1)

Description

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).

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

Last Updated: Oct 26, 2024