2-214809500-G-A

Position:

chr2-214809500-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000465.4(BARD1):c.70C>T(p.Pro24Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.363 in 1,603,114 control chromosomes in the GnomAD database, including 107,214 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P24R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.33 ( 8919 hom., cov: 34)

Exomes 𝑓: 0.37 ( 98295 hom. )

Consequence

BARD1
NM_000465.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.990

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026446283).

BP6

Variant 2-214809500-G-A is Benign according to our data. Variant chr2-214809500-G-A is described in ClinVar as [Benign]. Clinvar id is 183698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.394 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BARD1	NM_000465.4 linkuse as main transcript	c.70C>T	p.Pro24Ser	missense_variant	1/11	ENST00000260947.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BARD1	ENST00000260947.9 linkuse as main transcript	c.70C>T	p.Pro24Ser	missense_variant	1/11	1	NM_000465.4	P2	Q99728-1

Frequencies

GnomAD3 genomes

AF:

0.333

AC:

50590

AN:

152028

Hom.:

8911

Cov.:

show subpopulations

Gnomad AFR

AF:

0.212

Gnomad AMI

AF:

0.351

Gnomad AMR

AF:

0.386

Gnomad ASJ

AF:

0.436

Gnomad EAS

AF:

0.361

Gnomad SAS

AF:

0.409

Gnomad FIN

AF:

0.404

Gnomad MID

AF:

0.347

Gnomad NFE

AF:

0.370

Gnomad OTH

AF:

0.343

GnomAD3 exomes

AF:

0.384

AC:

87436

AN:

227958

Hom.:

16891

AF XY:

0.383

AC XY:

48186

AN XY:

125790

show subpopulations

Gnomad AFR exome

AF:

0.221

Gnomad AMR exome

AF:

0.432

Gnomad ASJ exome

AF:

0.427

Gnomad EAS exome

AF:

0.358

Gnomad SAS exome

AF:

0.409

Gnomad FIN exome

AF:

0.412

Gnomad NFE exome

AF:

0.377

Gnomad OTH exome

AF:

0.363

GnomAD4 exome

AF:

0.366

AC:

530737

AN:

1450966

Hom.:

98295

Cov.:

AF XY:

0.368

AC XY:

265225

AN XY:

721242

show subpopulations

Gnomad4 AFR exome

AF:

0.206

Gnomad4 AMR exome

AF:

0.425

Gnomad4 ASJ exome

AF:

0.418

Gnomad4 EAS exome

AF:

0.349

Gnomad4 SAS exome

AF:

0.413

Gnomad4 FIN exome

AF:

0.420

Gnomad4 NFE exome

AF:

0.362

Gnomad4 OTH exome

AF:

0.360

GnomAD4 genome

AF:

0.333

AC:

50616

AN:

152148

Hom.:

8919

Cov.:

AF XY:

0.336

AC XY:

24997

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.212

Gnomad4 AMR

AF:

0.386

Gnomad4 ASJ

AF:

0.436

Gnomad4 EAS

AF:

0.361

Gnomad4 SAS

AF:

0.409

Gnomad4 FIN

AF:

0.404

Gnomad4 NFE

AF:

0.370

Gnomad4 OTH

AF:

0.342

Alfa

AF:

0.363

Hom.:

3800

Bravo

AF:

0.322

TwinsUK

AF:

0.362

AC:

1343

ALSPAC

AF:

0.360

AC:

1386

ESP6500AA

AF:

0.215

AC:

892

ESP6500EA

AF:

0.347

AC:

2859

ExAC

AF:

0.367

AC:

43728

Asia WGS

AF:

0.375

AC:

1304

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial cancer of breast

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 25785002, 16061562, 27153395, 17028982, 19412175, 23222812, 23966609) -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 04, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	This alteration is classified as 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. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.066

T;.;.;.;T;.;.

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.69

T;T;T;T;T;T;.

MetaRNN

Benign

0.0026

T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;.;L;.;.;L;.

MutationTaster

Benign

0.61

P;P

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.2

N;.;.;.;.;.;N

REVEL

Benign

0.26

Sift

Benign

0.18

T;.;.;.;.;.;D

Sift4G

Benign

0.21

T;T;T;T;T;T;T

Polyphen

0.0020

B;.;.;.;.;.;.

Vest4

0.10

MPC

0.076

ClinPred

0.011

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.061

gMVP

0.25

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