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NM_000059.4(BRCA2):c.8893G>C (p.Asp2965His) AND Hereditary cancer-predisposing syndrome

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Jun 28, 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:
RCV000129723.11

Allele description [Variation Report for NM_000059.4(BRCA2):c.8893G>C (p.Asp2965His)]

NM_000059.4(BRCA2):c.8893G>C (p.Asp2965His)

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.8893G>C (p.Asp2965His)
HGVS:
  • NC_000013.11:g.32379455G>C
  • NG_012772.3:g.68976G>C
  • NM_000059.4:c.8893G>CMANE SELECT
  • NP_000050.2:p.Asp2965His
  • NP_000050.3:p.Asp2965His
  • LRG_293t1:c.8893G>C
  • LRG_293:g.68976G>C
  • LRG_293p1:p.Asp2965His
  • NC_000013.10:g.32953592G>C
  • NM_000059.3:c.8893G>C
  • U43746.1:n.9121G>C
  • p.D2965H
Protein change:
D2965H
Links:
dbSNP: rs80359141
NCBI 1000 Genomes Browser:
rs80359141
Molecular consequence:
  • NM_000059.4:c.8893G>C - 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

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000184528Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely benign
(Mar 26, 2018) 		germlineclinical testing

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

Citation Link,

SCV000906957Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain significance
(Jun 28, 2023) 		germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity.

Guidugli L, Pankratz VS, Singh N, Thompson J, Erding CA, Engel C, Schmutzler R, Domchek S, Nathanson K, Radice P, Singer C, Tonin PN, Lindor NM, Goldgar DE, Couch FJ.

Cancer Res. 2013 Jan 1;73(1):265-75. doi: 10.1158/0008-5472.CAN-12-2081. Epub 2012 Oct 29.

PubMed [citation]
PMID:
23108138
PMCID:
PMC3537884

Assessment of the Clinical Relevance of BRCA2 Missense Variants by Functional and Computational Approaches.

Guidugli L, Shimelis H, Masica DL, Pankratz VS, Lipton GB, Singh N, Hu C, Monteiro ANA, Lindor NM, Goldgar DE, Karchin R, Iversen ES, Couch FJ.

Am J Hum Genet. 2018 Feb 1;102(2):233-248. doi: 10.1016/j.ajhg.2017.12.013. Epub 2018 Jan 25.

PubMed [citation]
PMID:
29394989
PMCID:
PMC5985401
See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV000184528.7

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

Description

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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

From Color Diagnostics, LLC DBA Color Health, SCV000906957.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This missense variant replaces aspartic acid with histidine at codon 2965 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). Functional studies have reported that this variant has no impact on BRCA2 function in a homology-directed repair assay (PMID: 23108138, 29394989, 35736817). Multifactorial analysis has reported co-segregation, co-occurrence and family history likelihood ratios for pathogenicity of 1.00, 1.08 and 1.07, respectively (PMID: 23108138, 31131967). This variant also has been detected in a breast cancer case-control meta-analysis in 1/60463 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000381). This variant has not been identified 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

Last Updated: Sep 29, 2024