rs587781976

Positions:

chr2-214767641-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_000465.4(BARD1):c.1409A>G(p.Asn470Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000088 in 1,613,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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. N470Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000090 ( 0 hom. )

Consequence

BARD1
NM_000465.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:9

Conservation

PhyloP100: 1.73

Variant links:

Genes affected

BARD1 (HGNC:952): (BRCA1 associated RING domain 1) This gene encodes a protein which interacts with the N-terminal region of BRCA1. In addition to its ability to bind BRCA1 in vivo and in vitro, it shares homology with the 2 most conserved regions of BRCA1: the N-terminal RING motif and the C-terminal BRCT domain. The RING motif is a cysteine-rich sequence found in a variety of proteins that regulate cell growth, including the products of tumor suppressor genes and dominant protooncogenes. This protein also contains 3 tandem ankyrin repeats. The BARD1/BRCA1 interaction is disrupted by tumorigenic amino acid substitutions in BRCA1, implying that the formation of a stable complex between these proteins may be an essential aspect of BRCA1 tumor suppression. This protein may be the target of oncogenic mutations in breast or ovarian cancer. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2013]

BARD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.083332896).

BP6

Variant 2-214767641-T-C is Benign according to our data. Variant chr2-214767641-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141739.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Uncertain_significance=5, Benign=1}.

BS2

High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BARD1	NM_000465.4 linkuse as main transcript	c.1409A>G	p.Asn470Ser	missense_variant	6/11	ENST00000260947.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BARD1	ENST00000260947.9 linkuse as main transcript	c.1409A>G	p.Asn470Ser	missense_variant	6/11	1	NM_000465.4	P2	Q99728-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000104

AC:

AN:

251202

Hom.:

AF XY:

0.0000958

AC XY:

AN XY:

135746

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000462

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.0000896

AC:

131

AN:

1461712

Hom.:

Cov.:

AF XY:

0.0000894

AC XY:

AN XY:

727164

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000768

Gnomad4 NFE exome

AF:

0.0000666

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000129

Hom.:

Bravo

AF:

0.000117

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial cancer of breast

Uncertain:2Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 16, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 470 of the BARD1 protein (p.Asn470Ser). This variant is present in population databases (rs587781976, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer, endometrial cancer, ovarian cancer, and/or suspected Lynch syndrome (PMID: 14550946, 20077502, 25980754, 26315354). ClinVar contains an entry for this variant (Variation ID: 141739). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect BARD1 function (PMID: 18480049). 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. -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 24, 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]. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	research	University of Washington Department of Laboratory Medicine, University of Washington	May 09, 2018	The BARD1 variant designated as NM_000465.3:c.1409A>G (p.Asn470Ser) is classified as likely benign. This variant is listed in ClinVar (Variation ID: 141739) and has been classified as likely benign by another laboratory. The missense change resulting from this variant does not lead to structural defects in the protein (Fox et al, 2008, PMID: 18480049). Additionally, in one observed family, there are no BARD1-associated cancers reported for several individuals over age 50 who have or are at risk of having the variant. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives about a 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter BARD1 function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. -

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 31, 2024	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with BARD1-related and other cancers, but also in healthy controls (PMID: 33471991, 35534704, 20077502, 14550946, 26315354, 27443514, 35734982, 36187937); This variant is associated with the following publications: (PMID: 26738429, 15342711, 14550946, 20077502, 15855896, 19584272, 16633366, 23056176, 25980754, 27443514, 26315354, 27338793, 30374176, 34426522, 26787654, 31371347, 35734982, 36187937, 35949786, 18480049, 37418175, 33471991, 35534704) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 12, 2021	In the published literature, this variant has been reported in individuals with breast cancer (PMIDs: 14550946 (2003), 26787654 (2016), 35734982 (2022), 33471991 (2021); see also LOVD (https://databases.lovd.nl/shared/)), endometrial/ovarian cancer (PMIDs: 27443514 (2016), 26315354 (2015)), and suspected Lynch syndrome (PMID: 25980754 (2015)). In addition, this variant has been observed in healthy control individuals (PMIDs: 20077502 (2010), 33471991 (2021)), and in an individual with colon cancer who co-carried a pathogenic variant in the APC gene (PMID: 30374176 (2019)). This variant has been reported to have no observable defects to the crystal structure of the BARD1 ankyrin repeat domain, however the effect of this variant on protein function and activity were not assessed (PMID: 18480049 (2008)). The frequency of this variant in the general population, 0.00048 (12/25110 chromosomes in European (Finnish) subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. 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. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	BARD1: BP4, BP5, BS1 -

not specified

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 14, 2022	Variant summary: BARD1 c.1409A>G (p.Asn470Ser) results in a conservative amino acid change located in the Ankyrin repeat-containing domain (IPR020683) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. Additionally, Fox_2008 reports that this variant does not results in observable structural defects. The variant allele was found at a frequency of 0.00011 in 290022 control chromosomes, predominantly at a frequency of 0.00048 within the Finnish subpopulation in the gnomAD database and publications. The observed variant frequency within Finnish control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in BARD1 causing Breast Cancer phenotype (0.00025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Finnish origin. c.1409A>G has been reported in the literature in individuals affected with breast cancer, ovarian cancer or endometrial cancer as well as one individual who had a history of Lynch syndrome associated cancer and/or polyps, but has also been found in healthy controls (example, Ishitobi_2003, DeBrakeleer_2010, Yurgelun_2015, Ramus_2015, Young_2016, Ring_2016, Tsai_2019). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. At-least one co-occurrence with another pathogenic variant have been reported (APC c.220+2T>A, Tsai_2019), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments benign/likely benign, n=5; VUS, n=3). Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 08, 2019	This alteration is classified as likely 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	Nov 09, 2015	- -

Hereditary breast ovarian cancer syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Apr 19, 2022	- -
Likely benign, criteria provided, single submitter	curation	German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	Jan 17, 2024	Additional evidence agains pathogenicity from family/clinical data (see entries by Myriad and University of Washington). According to the ACMG standard criteria we chose these criteria: BP4 (supporting benign): CADD:15.07 REVEL: 0.17 BayesDEL:-0.584707, BS1 (supporting benign): gnomAD AF in FE -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.050

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Benign

0.76

DEOGEN2

Benign

0.11

T;.

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.81

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.86

D;D

M_CAP

Benign

0.013

MetaRNN

Benign

0.083

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.53

N;.

MutationTaster

Benign

0.75

D;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-2.3

N;.

REVEL

Benign

0.17

Sift

Benign

0.24

T;.

Sift4G

Benign

0.19

T;T

Polyphen

0.34

B;.

Vest4

0.15

MVP

0.68

MPC

0.11

ClinPred

0.045

GERP RS

0.28

Varity_R

0.21

gMVP

0.28

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