2-214809617-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000465.4(BARD1):c.-48T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.715 in 1,522,770 control chromosomes in the GnomAD database, including 390,559 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (41405 hom., cov: 36)
  • Exomes 𝑓: 0.71 (349154 hom.)
• Consequence: BARD1 NM_000465.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.58

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-214809617-A-G is Benign according to our data. Variant chr2-214809617-A-G is described in ClinVar as [Benign]. Clinvar id is 334200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.783 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BARD1	NM_000465.4	c.-48T>C		5_prime_UTR_variant	1/11	ENST00000260947.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BARD1	ENST00000260947.9	c.-48T>C		5_prime_UTR_variant	1/11	1	NM_000465.4	P2

Frequencies

GnomAD3 genomes AF: 0.737 AC: 112014 AN: 152012 Hom.: 41341 Cov.: 36

Gnomad AFR AF: 0.759

Gnomad AMI AF: 0.684

Gnomad AMR AF: 0.783

Gnomad ASJ AF: 0.722

Gnomad EAS AF: 0.804

Gnomad SAS AF: 0.667

Gnomad FIN AF: 0.763

Gnomad MID AF: 0.715

Gnomad NFE AF: 0.711

Gnomad OTH AF: 0.721

GnomAD3 exomes AF: 0.733 AC: 99849 AN: 136150 Hom.: 36910 AF XY: 0.725 AC XY: 53959 AN XY: 74456

Gnomad AFR exome AF: 0.765

Gnomad AMR exome AF: 0.815

Gnomad ASJ exome AF: 0.715

Gnomad EAS exome AF: 0.805

Gnomad SAS exome AF: 0.663

Gnomad FIN exome AF: 0.779

Gnomad NFE exome AF: 0.707

Gnomad OTH exome AF: 0.712

GnomAD4 exome AF: 0.713 AC: 976746 AN: 1370640 Hom.: 349154 Cov.: 39 AF XY: 0.711 AC XY: 478866 AN XY: 673634

Gnomad4 AFR exome AF: 0.761

Gnomad4 AMR exome AF: 0.810

Gnomad4 ASJ exome AF: 0.711

Gnomad4 EAS exome AF: 0.781

Gnomad4 SAS exome AF: 0.667

Gnomad4 FIN exome AF: 0.782

Gnomad4 NFE exome AF: 0.707

Gnomad4 OTH exome AF: 0.718

GnomAD4 genome AF: 0.737 AC: 112136 AN: 152130 Hom.: 41405 Cov.: 36 AF XY: 0.740 AC XY: 55004 AN XY: 74378

Gnomad4 AFR AF: 0.759

Gnomad4 AMR AF: 0.784

Gnomad4 ASJ AF: 0.722

Gnomad4 EAS AF: 0.804

Gnomad4 SAS AF: 0.668

Gnomad4 FIN AF: 0.763

Gnomad4 NFE AF: 0.711

Gnomad4 OTH AF: 0.724

Alfa AF: 0.722 Hom.: 7279

Bravo AF: 0.741

Asia WGS AF: 0.740 AC: 2571 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Familial cancer of breast Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	1.7
Dann	Benign	0.35

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

Other links and lift over

dbSNP: rs17489363; hg19: chr2-215674341;