NM_000059.4(BRCA2):c.8893G>C (p.Asp2965His) AND not specified

Germline classification:: Likely benign (2 submissions)
Last evaluated:: Jul 2, 2020
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000429093.2

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)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

Recent activity

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enoyl-[acyl-carrier-protein] reductase, mitochondrial isoform b [Homo sapiens]
enoyl-[acyl-carrier-protein] reductase, mitochondrial isoform b [Homo sapiens]
gi|1167503281|ref|NP_001019903.3|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000528641	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely benign (Jun 16, 2016)	germline	clinical testing	Citation Link,
SCV001426842	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Jul 2, 2020)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21990134, 23108138, 29580235, 29394989 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000528641

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely benign
(Jun 16, 2016)

germline

clinical testing

Citation Link,

SCV001426842

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Jul 2, 2020)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A review of a multifactorial probability-based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS).

Lindor NM, Guidugli L, Wang X, Vallée MP, Monteiro AN, Tavtigian S, Goldgar DE, Couch FJ.

Hum Mutat. 2012 Jan;33(1):8-21. doi: 10.1002/humu.21627. Epub 2011 Nov 3. Review.

PubMed [citation]

PMID:: 21990134
PMCID:: PMC3242438

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

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000528641.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001426842.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: BRCA2 c.8893G>C (p.Asp2965His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249982 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. Studies utilizing multifactorial likelihood models to assess the clinical significance of BRCA1/BRCA2 variants predict this variant to be likely non-pathogenic (e.g. Guidugli_2013, Lindor_2012). Experimental evidence evaluating an impact on protein function through utilization of a homologous recombination DNA-repair activity assay demonstrated the variant to be neutral/non-pathogenic (e.g. Guidugli_2013, 2018). Four ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=3) and as uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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