chr2-214781260-T-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000465.4(BARD1):c.614A>T(p.Lys205Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,442,508 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K205Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

BARD1
NM_000465.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.67

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

breast cancer
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
hereditary breast carcinoma
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
familial ovarian cancer
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
hereditary nonpolyposis colon cancer
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

BARD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BARD1	NM_000465.4 link	c.614A>T	p.Lys205Met	missense_variant	Exon 4 of 11	ENST00000260947.9	NP_000456.2	Q99728-1A0AVN2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9 link	c.614A>T	p.Lys205Met	missense_variant	Exon 4 of 11	1	NM_000465.4	ENSP00000260947.4		Q99728-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000432

AC:

AN:

231674

AF XY:

0.00000798

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

6.93e-7

AC:

AN:

1442508

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

716826

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31968

American (AMR)

AF:

0.00

AC:

AN:

39204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25180

East Asian (EAS)

AF:

0.00

AC:

AN:

39612

South Asian (SAS)

AF:

0.0000123

AC:

AN:

81038

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53116

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5640

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107270

Other (OTH)

AF:

0.00

AC:

AN:

59480

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Familial cancer of breast

Uncertain:1

Sep 09, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with BARD1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with methionine at codon 205 of the BARD1 protein (p.Lys205Met). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and methionine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

0.0086

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

T;.

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.77

T;T

M_CAP

Uncertain

0.20

MetaRNN

Uncertain

0.51

D;D

MetaSVM

Uncertain

0.23

MutationAssessor

Uncertain

2.6

M;.

PhyloP100

2.7

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-2.8

D;.

REVEL

Uncertain

0.45

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;.

Vest4

0.60

MutPred

0.41

Loss of helix (P = 0.0068);.;

MVP

0.95

MPC

0.47

ClinPred

0.95

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.27

gMVP

0.34

Mutation Taster

=84/16

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over