chr2-214809497-C-G

Position:

chr2-214809497-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_000465.4(BARD1):c.73G>C(p.Ala25Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000162 in 1,606,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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 0.000020 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

BARD1
NM_000465.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:1

Conservation

PhyloP100: -1.08

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 Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.27263042).

BS2

High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BARD1	NM_000465.4 linkuse as main transcript	c.73G>C	p.Ala25Pro	missense_variant	1/11	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.73G>C	p.Ala25Pro	missense_variant	1/11	1	NM_000465.4	ENSP00000260947.4		Q99728-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000389

AC:

AN:

231654

Hom.:

AF XY:

0.0000313

AC XY:

AN XY:

127714

show subpopulations

Gnomad AFR exome

AF:

0.000151

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000402

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:

0.0000158

AC:

AN:

1454414

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

723168

show subpopulations

Gnomad4 AFR exome

AF:

0.0000600

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000405

Gnomad4 SAS exome

AF:

0.0000351

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000333

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000959

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000334

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial cancer of breast

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 25 of the BARD1 protein (p.Ala25Pro). This variant is present in population databases (rs751646468, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with BARD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 185506). 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 have shown that this missense change does not substantially affect BARD1 function (PMID: 31371347). 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	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 12, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing;in vitro	Cancer Genetics Service, National Cancer Centre Singapore	May 01, 2019	- -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Feb 13, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 03, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 05, 2023	The c.73G>C (p.A25P) alteration is located in exon 1 (coding exon 1) of the BARD1 gene. This alteration results from a G to C substitution at nucleotide position 73, causing the alanine (A) at amino acid position 25 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The BARD1 p.Ala25Pro variant was not identified in the literature. The variant was identified in dbSNP (ID: rs751646468) â€šÃ„ÃºWith Uncertain significance alleleâ€šÃ„Ã¹, and ClinVar (classified as uncertain significance by Ambry Genetics and Invitae). The variant was identified in control databases in 9 of 258670 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017), observed in the following populations: African in 2 of 21472 chromosomes (freq: 0.00009) and East Asian in 7 of 18300 chromosomes (freq: 0.0004), while not observed in the Other, Latino, European Non-Finnish, Ashkenazi Jewish, European Finnish, and South Asian populations. The p.Ala25 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Pro to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.072

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

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.065

LIST_S2

Uncertain

0.87

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

M_CAP

Pathogenic

0.89

MetaRNN

Benign

0.27

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

MetaSVM

Benign

-0.42

MutationAssessor

Benign

1.4

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

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.2

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

REVEL

Uncertain

0.29

Sift

Benign

0.13

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

Sift4G

Benign

0.17

T;D;T;T;D;T;D

Polyphen

0.88

P;.;.;.;.;.;.

Vest4

0.12

MutPred

0.10

Gain of catalytic residue at P24 (P = 0.0148);Gain of catalytic residue at P24 (P = 0.0148);Gain of catalytic residue at P24 (P = 0.0148);Gain of catalytic residue at P24 (P = 0.0148);Gain of catalytic residue at P24 (P = 0.0148);Gain of catalytic residue at P24 (P = 0.0148);Gain of catalytic residue at P24 (P = 0.0148);

MVP

0.93

MPC

0.10

ClinPred

0.19

GERP RS

1.1

Varity_R

0.26

gMVP

0.34

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