NM_000059.4(BRCA2):c.7832A>G (p.Asp2611Gly) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 25, 2023
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:: RCV000165314.12

Allele description [Variation Report for NM_000059.4(BRCA2):c.7832A>G (p.Asp2611Gly)]

NM_000059.4(BRCA2):c.7832A>G (p.Asp2611Gly)

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.7832A>G (p.Asp2611Gly)

HGVS:

NC_000013.11:g.32362549A>G
NG_012772.3:g.52070A>G
NM_000059.4:c.7832A>GMANE SELECT
NP_000050.2:p.Asp2611Gly
NP_000050.3:p.Asp2611Gly
LRG_293t1:c.7832A>G
LRG_293:g.52070A>G
LRG_293p1:p.Asp2611Gly
NC_000013.10:g.32936686A>G
NM_000059.3:c.7832A>G
U43746.1:n.8060A>G
p.D2611G

Protein change:

D2611G

Links:

dbSNP: rs80359010

NCBI 1000 Genomes Browser:

rs80359010

Molecular consequence:

NM_000059.4:c.7832A>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

Recent activity

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Homo sapiens isolate csct_007801 mitochondrion, complete genome
Homo sapiens isolate csct_007801 mitochondrion, complete genome
gi|1150596877|gb|KY410223.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000216036	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Feb 21, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16030099, 19043619, 23108138, 29394989, 29884841 Citation Link,
SCV000683912	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 25, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 16030099, 23108138, 29394989, 32444794, 33293522, 35190686, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000216036

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Feb 21, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV000683912

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 25, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

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

Citations

PubMed

Classifying Variants of Undetermined Significance in BRCA2 with protein likelihood ratios.

Karchin R, Agarwal M, Sali A, Couch F, Beattie MS.

Cancer Inform. 2008;6:203-16. Epub 2008 Apr 18.

PubMed [citation]

PMID:: 19043619
PMCID:: PMC2587343

Comprehensive annotation of BRCA1 and BRCA2 missense variants by functionally validated sequence-based computational prediction models.

Hart SN, Hoskin T, Shimelis H, Moore RM, Feng B, Thomas A, Lindor NM, Polley EC, Goldgar DE, Iversen E, Monteiro ANA, Suman VJ, Couch FJ.

Genet Med. 2019 Jan;21(1):71-80. doi: 10.1038/s41436-018-0018-4. Epub 2018 Jun 8.

PubMed [citation]

PMID:: 29884841
PMCID:: PMC6287763

See all PubMed Citations (9)

Details of each submission

From Ambry Genetics, SCV000216036.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The p.D2611G variant (also known as c.7832A>G), located in coding exon 16 of the BRCA2 gene, results from an A to G substitution at nucleotide position 7832. The aspartic acid at codon 2611 is replaced by glycine, an amino acid with similar properties. In one study, this alteration was identified in 1/110 Hispanic patients with personal or family history of breast and/or ovarian cancer (Weitzel JN et al. Cancer Epidemiol. Biomarkers Prev., 2005 Jul;14:1666-71). This variant was found to be non-functional in a homology-directed DNA repair (HDR) assay (Hart SN et al. Genet. Med., 2019 01;21:71-80), while another HDR assay demonstrated p.D2611G to have intermediate functionality, with a probability of pathogenicity of 0.995 and a probability of neutrality of 0.005 (Guidugli L et al. Am. J. Hum. Genet., 2018 02;102:233-248). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.

#	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

From Color Diagnostics, LLC DBA Color Health, SCV000683912.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This missense variant replaces aspartic acid with glycine at codon 2611 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant impacts BRCA2 function in homology-mediated DNA repair assays (PMID: 23108138, 29394989), impacts cell viability in Brca2-deficient mouse embryonic stem cells (PMID: 33293522), increases sensitivity to DNA-damaging agents (PMID: 32444794), and was non-functional in a haploidized cell proliferation assay (PMID: 35190686). This variant has been reported in an individual with a personal or family history of breast or ovarian cancer (PMID: 16030099). This variant has been identified in 1/251200 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.

#	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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