NM_000059.4(BRCA2):c.7975A>G (p.Arg2659Gly) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jun 27, 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:: RCV000572654.15

Allele description [Variation Report for NM_000059.4(BRCA2):c.7975A>G (p.Arg2659Gly)]

NM_000059.4(BRCA2):c.7975A>G (p.Arg2659Gly)

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.7975A>G (p.Arg2659Gly)

HGVS:

NC_000013.11:g.32362692A>G
NG_012772.3:g.52213A>G
NM_000059.4:c.7975A>GMANE SELECT
NP_000050.2:p.Arg2659Gly
NP_000050.3:p.Arg2659Gly
LRG_293t1:c.7975A>G
LRG_293:g.52213A>G
LRG_293p1:p.Arg2659Gly
NC_000013.10:g.32936829A>G
NM_000059.3:c.7975A>G
U43746.1:n.8203A>G

Nucleotide change:

8203A>G

Protein change:

R2659G

Links:

dbSNP: rs80359026

NCBI 1000 Genomes Browser:

rs80359026

Molecular consequence:

NM_000059.4:c.7975A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000661425	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jun 16, 2023)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 15695382, 19043619, 21120943, 21523855, 22505045, 23108138, 24323938, 26489468, 28339459, 29310832, 29335924, 29394989, 31131967 Citation Link,
SCV006060950	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 27, 2023)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 22505045, 23108138, 28339459, 28905878, 29335924, 29394989, 29752822, 30254663, 31131967, 31191615, 32444794, 32850417, 33008098, 33801055, 34597585, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000661425

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jun 16, 2023)

germline

clinical testing

PubMed (13)
[See all records that cite these PMIDs]

Citation Link,

SCV006060950

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jun 27, 2023)

germline

clinical testing

PubMed (16)
[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

Functional evaluation and cancer risk assessment of BRCA2 unclassified variants.

Wu K, Hinson SR, Ohashi A, Farrugia D, Wendt P, Tavtigian SV, Deffenbaugh A, Goldgar D, Couch FJ.

Cancer Res. 2005 Jan 15;65(2):417-26.

PubMed [citation]

PMID:: 15695382

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

See all PubMed Citations (23)

Details of each submission

From Ambry Genetics, SCV000661425.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

The p.R2659G pathogenic mutation (also known as c.7975A>G), located in coding exon 16 of the BRCA2 gene, results from an A to G substitution at nucleotide position 7975. The arginine at codon 2659 is replaced by glycine, an amino acid with dissimilar properties. This alteration, along with close-match alteration BRCA2 c.7976G>A (p.R2659K) are located near a canonical splice donor site and result in in-frame, exon 16 skipping (Fraile-Bethencourt E et al. PLoS Genet. 2017 Mar;13:e1006691; Caux-Moncoutier V et al. Hum. Mutat. 2011 Mar;32:325-34; Houdayer C et al. Hum. Mutat. 2012 Aug;33:1228-38; Hofmann W et al. J Med Genet. 2003 Mar;40(3):e23). Both of these alterations are also non-functional in protein-based homology-directed DNA repair (HDR) assay (Guidugli L et al. Am. J. Hum. Genet. 2018 Jan; Wu K et al. Cancer Res. 2005 Jan;65:417-26; Guidugli L et al. Cancer Res. 2013 Jan;73:265-75). This alteration is considered pathogenic by multifactorial analysis that considers cosegregation, tumor pathology, co-occurrence with pathogenic mutation, family history and case-control data. Of note, the co-segregation likelihood ratio was particularly strong for this variant in this study (Parsons MT et al. Hum. Mutat., 2019 09;40:1557-1578). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Internal structural analysis suggests the arginine at codon 2659 closely interacts with other amino acids where other pathogenic substitutions have been identified. Further, the presence of a glycine at codon 2659 is likely to disrupt DNA binding (Ambry internal data). Based on the majority of available evidence to date, this alteration is interpreted as a disease-causing mutation.

#	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, SCV006060950.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

This missense variant replaces arginine with glycine at codon 2659 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 shown that this variant impacts BRCA2 function in a homology-directed repair assay and increases sensitivity to PARP inhibitors in mammalian cells (PMID: 23108138, 29394989, 32444794). RNA studies using patient-derived RNA and minigene assays have shown this variant causes partial in-frame skipping of exon 17 (PMID: 22505045, 28339459, 28905878, 31191615). This variant has been reported in at least seven individuals affected with breast or ovarian cancer (PMID: 29335924, 29752822, 30254663, 32850417, 33008098, 33801055, 31131967, 34597585). This variant has been reported in two multifactorial analyses with segregation likelihood ratios for pathogenicity of 1950.0 and 1,114.89 (PMID: 31131967, 34597585). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

#	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: May 16, 2025

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