rs80359010

chr13-32362549-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000059.4(BRCA2):c.7832A>G(p.Asp2611Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. D2611N) has been classified as Uncertain significance.

• 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 P:1 U:8 B:1
• Conservation: PhyloP100: 6.03

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 uncertain in NM_000059.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.7832A>G	p.Asp2611Gly	missense_variant	17/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.7832A>G	p.Asp2611Gly	missense_variant	17/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251200 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135778

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

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: 6.84e-7 AC: 1 AN: 1461732 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727178

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:8 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 20, 2023	This missense variant replaces aspartic acid with glycine at codon 2611 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 reported that this variant impacts BRCA2 function in homology-mediated DNA repair assays (PMID: 23108138, 29394989), impacts cell viability in Brca2-deficient mouse embryonic stem cells (PMID: 33293522), increases sensitivity to DNA-damaging agents (PMID: 32444794), and was non-functional in a haploidized cell proliferation assay (PMID: 35190686). This variant has been reported in an individual with a personal or family history of breast or ovarian cancer (PMID: 16030099). This variant has been identified in 1/251200 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Dec 23, 2003	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 06, 2023	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 14, 2016	- -

Hereditary breast ovarian cancer syndrome Pathogenic:1 Uncertain:1

Likely pathogenic, flagged submission	literature only	Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	Oct 04, 2018	Data used in classification The frequency of this variant is 1/123,000 individuals (the GNOMAD population). (PM2-mod). This variant is predicted deleterious on AlignGVGD (class: C65), SIFT (Deleterious), Polyphen2 HumVar (probably damaging) and CADD (27.1) (PP3-sup). The variant is in the DNA-binding domain of BRCA2 (PM1-sup). In the BRCA2 Homology-Directed Repair Activity assay for the DNA Binding Domain (Guidugli et al Cancer Res 2013;73:265-275,Couch Lab), which is perfectly validated against genetic epidemiologic data generated by ENIGMA, the variant has a probability of pathogenicity of 1.0 In the VarCall Bayesian statistical model for VUS classification using functional assay data (Guidugli et al Am J Hum Genet 2018; 102:233-248, Couch Lab), the variant has a probability of being deleterious of 0.879 and an overall classification of intermediate. (PS3-strong). Data not used in classification There are additional reports of this variant in ClinVar (5), BIC (1) and BRCA2 LOVD (2). -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 05, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 2611 of the BRCA2 protein (p.Asp2611Gly). This variant is present in population databases (rs80359010, gnomAD 0.003%). This missense change has been observed in individual(s) with a personal or family history of breast cancer (PMID: 16030099). ClinVar contains an entry for this variant (Variation ID: 52424). An algorithm developed specifically for the BRCA2 gene suggests that this missense change is likely to be tolerated (PMID: 19043619). Experimental studies have shown that this missense change affects BRCA2 function (PMID: 23108138, 29394989, 29884841, 33293522). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2017	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23108138, 17899372, 19043619, 16030099, 29394989, 29884841) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 28, 2021	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 21, 2023	The p.D2611G variant (also known as c.7832A>G), located in coding exon 16 of the BRCA2 gene, results from an A to G substitution at nucleotide position 7832. The aspartic acid at codon 2611 is replaced by glycine, an amino acid with similar properties. In one study, this alteration was identified in 1/110 Hispanic patients with personal or family history of breast and/or ovarian cancer (Weitzel JN et al. Cancer Epidemiol. Biomarkers Prev., 2005 Jul;14:1666-71). This variant was found to be non-functional in a homology-directed DNA repair (HDR) assay (Hart SN et al. Genet. Med., 2019 01;21:71-80), while another HDR assay demonstrated p.D2611G to have intermediate functionality, with a probability of pathogenicity of 0.995 and a probability of neutrality of 0.005 (Guidugli L et al. Am. J. Hum. Genet., 2018 02;102:233-248). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 25, 2023	This missense variant replaces aspartic acid with glycine at codon 2611 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 reported that this variant impacts BRCA2 function in homology-mediated DNA repair assays (PMID: 23108138, 29394989), impacts cell viability in Brca2-deficient mouse embryonic stem cells (PMID: 33293522), increases sensitivity to DNA-damaging agents (PMID: 32444794), and was non-functional in a haploidized cell proliferation assay (PMID: 35190686). This variant has been reported in an individual with a personal or family history of breast or ovarian cancer (PMID: 16030099). This variant has been identified in 1/251200 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Pathogenic	0.93	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.9	N;N
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.74
MutPred		0.69		Gain of methylation at K2613 (P = 0.045);Gain of methylation at K2613 (P = 0.045);
MVP		0.98
MPC		0.17
ClinPred		0.91	D
GERP RS		5.7
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs80359010; hg19: chr13-32936686;