chr13-32363393-C-G

Variant names:

• chr13-32363393-C-G
• rs397507966
• NM_000059.4:c.8191C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000059.4(BRCA2):​c.8191C>G​(p.Gln2731Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Q2731R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 3.80
• Publications: 7 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 17 benign, 24 uncertain in NM_000059.4
• PM2: Very rare variant in population databases, with high coverage

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.8191C>G	p.Gln2731Glu	missense	Exon 18 of 27	NP_000050.3
	BRCA2	NM_001432077.1		c.8191C>G	p.Gln2731Glu	missense	Exon 18 of 27	NP_001419006.1
	BRCA2	NM_001406720.1		c.8191C>G	p.Gln2731Glu	missense	Exon 18 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.8191C>G	p.Gln2731Glu	missense	Exon 18 of 27	ENSP00000369497.3
	BRCA2	ENST00000544455.6	TSL:1	c.8191C>G	p.Gln2731Glu	missense	Exon 18 of 27	ENSP00000439902.1
	BRCA2	ENST00000530893.7	TSL:1	c.7822C>G	p.Gln2608Glu	missense	Exon 18 of 27	ENSP00000499438.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461866 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727228

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Uncertain:3

Oct 31, 2023

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 28, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 236914). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 2731 of the BRCA2 protein (p.Gln2731Glu).

Jul 02, 2018

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Apr 22, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting, BP4 c.8191C>G, located in a (potentially) clinically important functional domain of BRCA2, is predicted to result in the substitution of Glutamine by Glutamic Acid at codon 2731, p.(Gln2731Glu). It is not present in the population database gnomAD v2.1.1, non cancer dataset (PM2_supporting). The SpliceAI algorithm predicts no significant impact on splicing and the BayesDel_noAF predictor score for this variant (-0.043) suggests that it does not affect the protein function (BP4). This alteration was identified in a multifactorial analysis showing a Combined LR for clinical data 0.977, co-occurrence LR 1.025 and family history LR 0.954 (PMID: 31131967). To our knowledge, neither relevant clinical data nor well-stablished functional studies have been reported for this variant. In addition, it has been identified in the ClinVar database (5x as uncertain significance), and BRCA Exchange database (not yet reviewed), but it is not present in the LOVD database. Based on the currently available information, c.8191C>G is classified as an uncertain significance variant according to ClinGen-BRCA2 Guidelines version 1.

May 08, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

not provided Uncertain:1

Jan 12, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 8419C>G; This variant is associated with the following publications: (PMID: 12228710, 31131967)

Familial cancer of breast Uncertain:1

Jan 19, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	18
DANN	Uncertain	0.99
Eigen	Benign	-0.0020
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.58	T
PhyloP100		3.8
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.78	N
REVEL	Uncertain	0.47
Sift	Uncertain	0.024	D
Sift4G	Benign	0.19	T
Vest4		0.42
MutPred		0.69		Loss of helix (P = 0.0626)
MVP		0.93
MPC		0.032
ClinPred		0.55	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.51
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397507966; hg19: chr13-32937530;