13-32339349-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000059.4(BRCA2):c.4994A>G(p.Glu1665Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. E1665Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 1.32

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.4994A>G	p.Glu1665Gly	missense_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.4994A>G	p.Glu1665Gly	missense_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 45

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 19, 2021	The p.E1665G variant (also known as c.4994A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 4994. The glutamic acid at codon 1665 is replaced by glycine, an amino acid with similar properties. This alteration was identified in an individual diagnosed with breast cancer (Abulkhair O et al. J Glob Oncol, 2018 08;4:1-9). This amino acid position is not well 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. -
Likely benign, criteria provided, single submitter	curation	University of Washington Department of Laboratory Medicine, University of Washington	Mar 23, 2023	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 29, 2019	- -

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jun 06, 2023

This sequence change replaces Glutamic acid with Glycine at codon 1665 of th BRCA2 protein (p.Glu1665Gly ) also known as c.4994A>G, which located in coding exon 11 of the BRCA2 gene(NM_000059.3), results from a A to G substitution at nucleotide position 4994. This amino acid position is not highly conserved. This variant is not present in population databases ( Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), 1000 Genomes Project and gnomAD). ClinVar contains an entry for this variant (Variation ID: 462363). Several computational methods predict this alteration to be benign based on seven benign predictions from (BayesDel_addAF, DANN, EIGEN, FATHMM-MKL, MutationTaster, PrimateAI and PolyPhen ) vs three pathogenic predictions from (M-CAP , MVP and SIFT). 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Apr 13, 2021

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 03, 2023

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. 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. ClinVar contains an entry for this variant (Variation ID: 462363). This missense change has been observed in individual(s) with breast cancer (PMID: 30199306). This variant is present in population databases (rs777981245, gnomAD 0.0009%). This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1665 of the BRCA2 protein (p.Glu1665Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	15
Dann	Benign	0.97
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.32	N
M_CAP	Uncertain	0.095	D
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Benign	-0.75	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Uncertain	0.32
Sift	Benign	0.058	T;T
Sift4G	Uncertain	0.0080	D;D
Vest4		0.40
MutPred		0.65		Loss of stability (P = 0.0312);Loss of stability (P = 0.0312);
MVP		0.93
MPC		0.022
ClinPred		0.084	T
GERP RS		1.9
gMVP		0.22

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

Publications

LitVar

Other links and lift over

dbSNP: rs777981245; hg19: chr13-32913486;