13-32333303-C-G

Position:

• chr13-32333303-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000059.4(BRCA2):​c.1825C>G​(p.Gln609Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,453,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:1
• Conservation: PhyloP100: 0.774

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13255405).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.1825C>G	p.Gln609Glu	missense_variant	10/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.1825C>G	p.Gln609Glu	missense_variant	10/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.1456C>G	p.Gln486Glu	missense_variant	10/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.1825C>G		non_coding_transcript_exon_variant	9/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000416 AC: 1 AN: 240112 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 130406

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000560

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1453250 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 722712

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.00144 AC: 5 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 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	Color Diagnostics, LLC DBA Color Health	Dec 14, 2022	This missense variant replaces glutamine with glutamic acid at codon 609 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 been reported in individuals affected with breast cancer and in an unaffected control individual (PMID: 17972177, 18627636, 28222693). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 8/60466 cases and 4/53461 controls; OR=1.768 (95%CI 0.532 to 5.873); Leiden Open Variation Database DB-ID BRCA2_001923 (PMID: 33471991). This variant has been identified in 1/240112 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. -
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	Ambry Genetics	Oct 07, 2024	The p.Q609E variant (also known as c.1825C>G), located in coding exon 9 of the BRCA2 gene, results from a C to G substitution at nucleotide position 1825. The glutamine at codon 609 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration has been reported in two individuals of Indonesian and Malay decent with a history of early-onset breast cancer (Purnomosari D et al. Breast Cancer Res. Treat. 2007; 106:297-304, Thirthagiri E et al. Breast Cancer Res. 2008; 10:R59). In a large case-control study using multi-ethnic Asian cohorts, this variant was detected in 2/1218 breast cancer patients and 1/1464 healthy controls (Lai KN et al. BMC Cancer, 2017 02;17:149).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. Based on the available evidence, the clinical significance of this variant remains unclear. -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 13, 2021	Variant summary: BRCA2 c.1825C>G (p.Gln609Glu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-06 in 240112 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1825C>G has been reported in the literature in individuals affected breast cancer (Lai_2017, Purnomosari_2007, Thirthagiri_2008) but as well as in controls (Lai_2017). These reports however, do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. Co-occurrence with another pathogenic variant has been reported (BRCA2 c.4631delA, p.Asn1544ThrfsX24; internal database), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2016	- -

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

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Sep 18, 2010	- -
Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 24, 2011	- -

BRCA2-related cancer predisposition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jul 10, 2024

This missense variant replaces glutamine with glutamic acid at codon 609 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer and in an unaffected control individual (PMID: 17972177, 18627636, 28222693). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 8/60466 cases and 4/53461 controls; OR=1.768 (95%CI 0.532 to 5.873); Leiden Open Variation Database DB-ID BRCA2_001923 (PMID: 33471991). This variant has been identified in 1/240112 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 05, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as 2053C>G; This variant is associated with the following publications: (PMID: 28222693, 10923033, 18627636, 17972177, 29884841, 31853058, 29684080, 32377563, 33471991, 32467295, 39440754) -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2024

This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 609 of the BRCA2 protein (p.Gln609Glu). This variant is present in population databases (rs80358472, gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer and an unaffected control individual (PMID: 17972177, 18627636, 28222693). This variant is also known as 2053C>G. ClinVar contains an entry for this variant (Variation ID: 51208). 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 with a negative predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	19
DANN	Uncertain	0.98
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.097	N
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.96	T
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.68	N;N
REVEL	Benign	0.20
Sift	Uncertain	0.0040	D;D
Sift4G	Benign	0.22	T;T
Vest4		0.33
MutPred		0.14		Gain of ubiquitination at K610 (P = 0.026);Gain of ubiquitination at K610 (P = 0.026);
MVP		0.88
MPC		0.021
ClinPred		0.11	T
GERP RS		3.7
gMVP		0.21

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: rs80358472; hg19: chr13-32907440;