rs80358520

Positions:

Variant summary

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

The NM_000059.4(BRCA2):c.2561A>G(p.Asn854Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000622 in 1,606,662 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. N854D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:2

Conservation

PhyloP100: 1.19

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=0.13297758).

BP6

Variant 13-32336916-A-G is Benign according to our data. Variant chr13-32336916-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 51306.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=6}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.2561A>G	p.Asn854Ser	missense_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.2561A>G	p.Asn854Ser	missense_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000205

AC:

AN:

243382

Hom.:

AF XY:

0.0000152

AC XY:

AN XY:

131480

show subpopulations

Gnomad AFR exome

AF:

0.000125

Gnomad AMR exome

AF:

0.0000916

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:

0.00000344

AC:

AN:

1454466

Hom.:

Cov.:

AF XY:

0.00000415

AC XY:

AN XY:

723046

show subpopulations

Gnomad4 AFR exome

AF:

0.0000608

Gnomad4 AMR exome

AF:

0.0000698

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:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.000121

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 03, 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, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 30, 2018	- -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 10, 2024	The p.N854S variant (also known as c.2561A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 2561. The asparagine at codon 854 is replaced by serine, an amino acid with highly similar properties. 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	Nov 22, 2022	This missense variant replaces asparagine with serine at codon 854 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 that this variant protein does not increase the sensitivity to PARP inhibitors in mammalian cells compared to the wild-type protein (PMID: 32444794). This variant has not been reported in individuals affected with BRCA2-related disorders in the literature. This variant has been identified in 7/274788 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:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 05, 2023	Observed in individuals referred for hereditary cancer multi-gene panel testing (Li et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 2789A>G; This variant is associated with the following publications: (PMID: 32377563, 29884841, 31911673, 30630528, 31853058) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 18, 2023	In the published literature, this variant has been reported in a coldspot region within BRCA2 where missense variants are unlikely to be pathogenic (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.00012 (3/24724 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity, however it has been seen in cancer free women over the age of 50 (FLOSSIES, https://whi.color.com). 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. -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 26, 2023

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 854 of the BRCA2 protein (p.Asn854Ser). This variant is present in population databases (rs80358520, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 51306). 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

0.16

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.19

M_CAP

Benign

0.022

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-4.0

D;D

REVEL

Benign

0.051

Sift

Uncertain

0.018

D;D

Sift4G

Benign

0.52

T;T

Vest4

0.34

MVP

0.72

MPC

0.033

ClinPred

0.073

GERP RS

1.3

gMVP

0.26

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