rs587781794

Positions:

Variant summary

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

The NM_000059.4(BRCA2):c.1666A>G(p.Asn556Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,790 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. N556H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:3

Conservation

PhyloP100: 0.0810

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=0.06895709).

BP6

Variant 13-32333144-A-G is Benign according to our data. Variant chr13-32333144-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141498.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=6}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.1666A>G	p.Asn556Asp	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.1666A>G	p.Asn556Asp	missense_variant	10/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251222

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135790

show subpopulations

Gnomad AFR exome

AF:

0.0000616

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461790

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 01, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 12, 2023	The p.N556D variant (also known as c.1666A>G), located in coding exon 9 of the BRCA2 gene, results from an A to G substitution at nucleotide position 1666. The asparagine at codon 556 is replaced by aspartic acid, an amino acid with highly similar properties. In a study of 359 breast cancer patients and 66 ovarian cancer patients in the Hakka population in southern China, this alteration was identified in a patient with breast cancer (Wu H et al. Hum Hered, 2019 Feb;84:160-169). In another study, this variant was reported in 3/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med 2021 02;384:428-439). This amino acid position is poorly 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	Aug 14, 2023	Identified in individuals with breast or ovarian cancer and in unaffected controls (Wu et al., 2019; Dorling et al., 2021; Zhang et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 1894A>G; This variant is associated with the following publications: (PMID: 25348012, 22505045, 32101877, 31131967, 33471991, 35918668) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 07, 2023	The frequency of this variant in the general population, 0.000004 (1/251222 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 (PMIDs: 32101877 (2019) and 33471991 (2021), http://databases.lovd.nl/shared/genes/BRCA2), as well as healthy individuals (PMID: 33471991 (2021), http://databases.lovd.nl/shared/genes/BRCA2). A functional study using a minigene assay reported that the variant had no effect on splicing (PMID: 22505045 (2012)). 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

Jul 08, 2021

Variant summary: BRCA2 c.1666A>G (p.Asn556Asp) 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 4e-06 in 251222 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1666A>G has been reported in the literature in individuals affected with breast cancer (e.g. Wu_2019, Dorling_2021) but it has also been reported in controls (e.g. Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A co-occurrence with a pathogenic variant has been reported (BRCA2 c.4093delT, p.Cys1365ValfsX9; UMD), providing supporting evidence for a benign role. Experimental evidence demonstrated the variant does not affect splicing (Houdayer_2012). Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and one ClinVar submitter (evaluation after 2014) cites it as likely benign. A recent publication involving the ENIGMA network of collaborators (Parsons_2019) assigned a classification of uncertain significance based on likelihood ratios (LRs) for pathogenicity estimated from clinical data of co-occurrence, family history and bioinformatic predictions; however, no evidence was provided for independent assessment. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

BRCA2-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 04, 2023

The BRCA2 c.1666A>G variant is predicted to result in the amino acid substitution p.Asn556Asp. This variant was reported in 4 individuals with breast cancer (Dorling et al 2021. PubMed ID: 33471991; Wu et al 2019. PubMed ID: 32101877) and in 2 control individuals (Dorling et al 2021. PubMed ID: 33471991). Experimental evidence demonstrated the variant does not affect splicing (Houdayer et al 2012. PubMed ID: 22505045). A recent publication involving the ENIGMA network of collaborators (Parsons et al 2019. PubMed ID: 31131967) assigned a classification of uncertain significance to this variant. This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Familial cancer of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Center for Precision Medicine, Meizhou People's Hospital

- -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 556 of the BRCA2 protein (p.Asn556Asp). This variant is present in population databases (rs587781794, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer (PMID: 32101877). ClinVar contains an entry for this variant (Variation ID: 141498). 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. -

Breast-ovarian cancer, familial, susceptibility to, 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Oct 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.54

CADD

Benign

1.3

DANN

Benign

0.19

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.075

M_CAP

Benign

0.035

MetaRNN

Benign

0.069

T;T

MetaSVM

Benign

-0.94

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.51

N;N

REVEL

Uncertain

0.36

Sift

Benign

0.12

T;T

Sift4G

Benign

0.92

T;T

Vest4

0.10

MutPred

0.15

Gain of disorder (P = 0.1572);Gain of disorder (P = 0.1572);

MVP

0.68

MPC

0.040

ClinPred

0.065

GERP RS

1.7

gMVP

0.046

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