13-32340831-A-G

Variant names:

• chr13-32340831-A-G
• rs763486267
• NM_000059.4:c.6476A>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000059.4(BRCA2):​c.6476A>G​(p.Gln2159Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000696 in 1,437,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q2159H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 4.43
• Publications: 5 publications found

Genes affected

BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]

BRCA2 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• Fanconi anemia complementation group D1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• pancreatic cancer, susceptibility to, 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• medulloblastoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19789612).
• BP6: Variant 13-32340831-A-G is Benign according to our data. Variant chr13-32340831-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 409447.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000059.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	NM_000059.4	MANE Select	c.6476A>G	p.Gln2159Arg	missense	Exon 11 of 27	NP_000050.3
	BRCA2	NM_001432077.1		c.6476A>G	p.Gln2159Arg	missense	Exon 11 of 27	NP_001419006.1
	BRCA2	NM_001406720.1		c.6476A>G	p.Gln2159Arg	missense	Exon 11 of 27	NP_001393649.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.6476A>G	p.Gln2159Arg	missense	Exon 11 of 27	ENSP00000369497.3
	BRCA2	ENST00000544455.6	TSL:1	c.6476A>G	p.Gln2159Arg	missense	Exon 11 of 27	ENSP00000439902.1
	BRCA2	ENST00000530893.7	TSL:1	c.6107A>G	p.Gln2036Arg	missense	Exon 11 of 27	ENSP00000499438.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000435 AC: 1 AN: 229630 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000931

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1437812 Hom.: 0 Cov.: 46 AF XY: 0.00 AC XY: 0 AN XY: 714024

African (AFR) AF: 0.00 AC: 0 AN: 31874

American (AMR) AF: 0.00 AC: 0 AN: 38522

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24900

East Asian (EAS) AF: 0.00 AC: 0 AN: 39496

South Asian (SAS) AF: 0.00 AC: 0 AN: 81102

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52818

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5622

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104206

Other (OTH) AF: 0.0000169 AC: 1 AN: 59272

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Jul 17, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glutamine with arginine at codon 2159 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 not been reported in individuals affected with BRCA2-related disorders in the literature. This variant has been identified in 1/229630 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.

Sep 11, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q2159R variant (also known as c.6476A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 6476. The glutamine at codon 2159 is replaced by arginine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6499 samples (12998 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.0003% (greater than 300000 alleles tested) in our clinical cohort. This amino acid position is poorly 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.

Mar 23, 2023

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

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

Hereditary breast ovarian cancer syndrome Uncertain:1

Jun 09, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA2-related disease. This sequence change replaces glutamine with arginine at codon 2159 of the BRCA2 protein (p.Gln2159Arg). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and arginine.

not specified Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	15
DANN	Benign	0.76
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.64
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.93	T
PhyloP100		4.4
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.15	N
REVEL	Uncertain	0.32
Sift	Benign	0.13	T
Sift4G	Uncertain	0.058	T
Vest4		0.17
MutPred		0.32		Gain of MoRF binding (P = 0.0413)
MVP		0.88
MPC		0.021
ClinPred		0.038	T
GERP RS		4.2
gMVP		0.12
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs763486267; hg19: chr13-32914968;