rs276174810

chr13-32333078-G-Achr13-32333078-G-Cchr13-32333078-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_000059.4(BRCA2):c.1600G>A(p.Glu534Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,611,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign 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. E534G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:2

Conservation

PhyloP100: 0.323

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07107511).

BP6

Variant 13-32333078-G-A is Benign according to our data. Variant chr13-32333078-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 37749.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=7, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.1600G>A	p.Glu534Lys	missense_variant	10/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.1600G>A	p.Glu534Lys	missense_variant	10/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

248706

Hom.:

AF XY:

0.0000223

AC XY:

AN XY:

134404

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000219

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:

0.00000206

AC:

AN:

1459422

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725890

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152274

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000330

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:4

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)	Jul 12, 2010	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 16, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 08, 2023	This missense variant replaces glutamic acid with lysine at codon 534 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). A functional study has shown this variant does not impact cell viability or sensitivity to DNA-damaging agents (PMID: 33314489). This variant has been reported in at least two individuals affected with breast cancer and two unaffected individuals (PMID: 18627636, 33314489, 33471991; Leiden Open Variation Database DB-ID BRCA2_007646). This variant has been identified in 4/248706 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. -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 26, 2023	This missense variant replaces glutamic acid with lysine at codon 534 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). A functional study has shown this variant does not impact cell viability or sensitivity to DNA-damaging agents (PMID: 33314489). This variant has been reported in at least two individuals affected with breast cancer and two unaffected individuals (PMID: 18627636, 33314489, 33471991; Leiden Open Variation Database DB-ID BRCA2_007646). This variant has been identified in 4/248706 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, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 30, 2021	The p.E534K variant (also known as c.1600G>A), located in coding exon 9 of the BRCA2 gene, results from a G to A substitution at nucleotide position 1600. The glutamic acid at codon 534 is replaced by lysine, an amino acid with similar properties. This alteration was observed in a series of 187 Malaysian women with breast cancer who were diagnosed under age 40 or had strong family history of breast or ovarian cancer (Thirthagiri E etal. Breast Cancer Res. 2008;10:R5 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). -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 24, 2018	This variant is denoted BRCA2 c.1600G>A at the cDNA level, p.Glu534Lys (E534K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant, previously published as 1828G>A using alternate nomenclature, has been reported in at least one individual with breast cancer (Thirthagiri 2008). BRCA2 Glu534Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Glu534Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 12, 2022	The frequency of this variant in the general population, 0.00022 (4/18270 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer as well as in a healthy control (PMIDs: 33314489 (2021), 18627636 (2008)). A functional study showed an ability of the variant to rescue Brca2-null mouse embryonic stem cells (mESC) and no sensitivity to DNA damaging agents (PMID: 33314489 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 22, 2023

Variant summary: BRCA2 c.1600G>A (p.Glu534Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.7e-05 in 271478 control chromosomes (gnomAD, Dong_2021). This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (3.7e-05 vs 0.00075), allowing no conclusion about variant significance. c.1600G>A has been reported in the literature in individuals affected withbreast cancer without any evidence for causality (Thirthagiri_2008, Dorling_2021, Sullivan_2021), therefore, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. One publication using Brca2 deficient mouse embryonic stem cells showed no damaging effects of this variant: the variant could rescue cell viability and was not sensative to DNA damaging agents (Sullivan_2021). The following publications have been ascertained in the context of this evaluation (PMID: 32467295, 33314489, 18627636, 33471991). Seven ClinVar submitters have assessed this variant since 2014: six classified the variant as uncertain significance and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary breast ovarian cancer syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 11, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.31

Cadd

Benign

9.3

Dann

Benign

0.93

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.15

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.071

T;T

MetaSVM

Benign

-0.95

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.55

N;N

REVEL

Benign

0.21

Sift

Benign

0.20

T;T

Sift4G

Uncertain

0.015

D;D

Vest4

0.30

MutPred

0.094

Gain of ubiquitination at E534 (P = 0.0082);Gain of ubiquitination at E534 (P = 0.0082);

MVP

0.65

MPC

0.022

ClinPred

0.043

GERP RS

3.7

gMVP

0.14

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over