chr2-214792353-C-T

Position:

chr2-214792353-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000465.4(BARD1):c.308G>A(p.Ser103Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000366 in 1,613,096 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).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

BARD1
NM_000465.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:4

Conservation

PhyloP100: 0.660

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:

BARD1 (HGNC:):

BARD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.032180548).

BP6

Variant 2-214792353-C-T is Benign according to our data. Variant chr2-214792353-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 142216.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=7, Benign=1}.

BS2

High AC in GnomAd4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BARD1	NM_000465.4 linkuse as main transcript	c.308G>A	p.Ser103Asn	missense_variant	3/11	ENST00000260947.9	NP_000456.2	Q99728-1A0AVN2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9 linkuse as main transcript	c.308G>A	p.Ser103Asn	missense_variant	3/11	1	NM_000465.4	ENSP00000260947.4		Q99728-1

Frequencies

GnomAD3 genomes

AF:

0.000178

AC:

AN:

151606

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000631

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:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251182

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135758

show subpopulations

Gnomad AFR exome

AF:

0.000492

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:

0.0000205

AC:

AN:

1461374

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

726978

show subpopulations

Gnomad4 AFR exome

AF:

0.000628

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:

0.00

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000191

AC:

AN:

151722

Hom.:

Cov.:

AF XY:

0.000189

AC XY:

AN XY:

74130

show subpopulations

Gnomad4 AFR

AF:

0.000677

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:

0.0000757

Hom.:

Bravo

AF:

0.000181

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial cancer of breast

Uncertain:3Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jul 19, 2024	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, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 103 of the BARD1 protein (p.Ser103Asn). This variant is present in population databases (rs145629242, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer (PMID: 35264596). ClinVar contains an entry for this variant (Variation ID: 142216). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BARD1 function (PMID: 30925164). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 22, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 31, 2020	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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Feb 13, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Nov 05, 2024	The missense variant NM_000465.4(BARD1):c.308G>A (p.Ser103Asn) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The variant is observed in one or more well-documented healthy adults. There is a small physicochemical difference between serine and asparagine, which is not likely to impact secondary protein structure as these residues share similar properties. For these reasons, this variant has been classified as Uncertain Significance. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 06, 2022	- -

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 2023	Published functional studies demonstrate homology-directed repair activity comparable to wild-type (PMID: 30925164); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18480049, 14647430, 33471991, 35264596, 30925164) -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 04, 2022	- -

BARD1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 11, 2023

The BARD1 c.308G>A variant is predicted to result in the amino acid substitution p.Ser103Asn. This variant was reported in an individual with cancer; however, in vitro analysis in a homology-directed repair assay indicated the resulting protein functioned similar to wild type (Adamovich et al. 2019. PubMed ID: 30925164). This variant is reported in 0.060% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-215657077-C-T). In ClinVar, this variant has been interpreted as 'uncertain' or 'likely benign' by outside laboratories (https://preview.ncbi.nlm.nih.gov/clinvar/variation/142216/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.58

CADD

Benign

9.9

DANN

Benign

0.97

DEOGEN2

Benign

0.043

T;.;.;.

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.70

T;T;T;T

M_CAP

Benign

0.0083

MetaRNN

Benign

0.032

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.49

N;.;.;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.010

N;.;.;.

REVEL

Benign

0.13

Sift

Benign

0.57

T;.;.;.

Sift4G

Benign

0.65

T;T;T;T

Polyphen

0.0020

B;.;.;.

Vest4

0.16

MVP

0.78

MPC

0.073

ClinPred

0.064

GERP RS

3.1

Varity_R

0.19

gMVP

0.21

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