rs80358466

chr13-32333282-G-Achr13-32333282-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The NM_000059.4(BRCA2):c.1804G>A(p.Gly602Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000618 in 1,602,592 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 Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G602V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:16
• Conservation: PhyloP100: 2.46

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19869363).
• BP6: Variant 13-32333282-G-A is Benign according to our data. Variant chr13-32333282-G-A is described in ClinVar as [Benign]. Clinvar id is 51200.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32333282-G-A is described in Lovd as [Benign]. Variant chr13-32333282-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.1804G>A	p.Gly602Arg	missense_variant	10/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.1804G>A	p.Gly602Arg	missense_variant	10/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151784 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000418 AC: 10 AN: 239120 Hom.: 0 AF XY: 0.0000540 AC XY: 7 AN XY: 129660

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000915

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000662 AC: 96 AN: 1450808 Hom.: 0 Cov.: 35 AF XY: 0.0000651 AC XY: 47 AN XY: 721496

Gnomad4 AFR exome AF: 0.0000307

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000389

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000812

Gnomad4 OTH exome AF: 0.0000501

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151784 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74106

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000900 Hom.: 0

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:16

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1 Benign:7

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jan 15, 2010	- -
Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Aug 10, 2015	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000000101 -
Benign, criteria provided, single submitter	clinical testing	Counsyl	May 03, 2016	- -
Benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Feb 20, 2004	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 23, 2019	Variant summary: BRCA2 c.1804G>A (p.Gly602Arg) results in a non-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-05 in 239200 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (4.2e-05 vs 0.00075), allowing no conclusion about variant significance. c.1804G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Lee_2008, Soegaard_2008, Borg_2010, Balabas_2010, Stegel_2011). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.5263_5264insC, p.Ser1755?fs; BRCA1 c.2679_2682delGAAA, p.Lys893_Lys894?fs in the BIC database; BRCA2 c.7558C>T , p.Arg2520Ter in a patient tested at our laboratory), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 24, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	This variant is associated with the following publications: (PMID: 24323938, 20104584, 20383589, 21218378, 21990134, 28678401, 21232165, 18559594, 23034506, 17924331, 27300552, 32444794, 32123317) -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 19, 2014	This alteration is classified as 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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 16, 2015	- -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 20, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	17
Dann	Uncertain	0.98
Eigen	Benign	-0.068
Eigen_PC	Benign	-0.021
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.95	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.17
Sift	Benign	0.13	T;T
Sift4G	Benign	0.17	T;T
Vest4		0.22
MutPred		0.16		Gain of methylation at K603 (P = 0.0436);Gain of methylation at K603 (P = 0.0436);
MVP		0.86
MPC		0.023
ClinPred		0.087	T
GERP RS		3.6
gMVP		0.13

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: rs80358466; hg19: chr13-32907419;