2-214792458-TAAAA-TAA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_000465.4(BARD1):c.216-15_216-14del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0839 in 1,359,760 control chromosomes in the GnomAD database, including 507 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.062 (223 hom., cov: 0)
  • Exomes 𝑓: 0.086 (284 hom.)
• Consequence: BARD1 NM_000465.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.804

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 -9 ACMG points.

• BP6: Variant 2-214792458-TAA-T is Benign according to our data. Variant chr2-214792458-TAA-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 334196.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=1}.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0904 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BARD1	NM_000465.4	c.216-15_216-14del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000260947.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BARD1	ENST00000260947.9	c.216-15_216-14del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000465.4	P2

Frequencies

GnomAD3 genomes AF: 0.0617 AC: 7844 AN: 127182 Hom.: 217 Cov.: 0

Gnomad AFR AF: 0.0529

Gnomad AMI AF: 0.00783

Gnomad AMR AF: 0.0938

Gnomad ASJ AF: 0.0589

Gnomad EAS AF: 0.000947

Gnomad SAS AF: 0.0516

Gnomad FIN AF: 0.0571

Gnomad MID AF: 0.0692

Gnomad NFE AF: 0.0659

Gnomad OTH AF: 0.0666

GnomAD3 exomes AF: 0.111 AC: 10714 AN: 96390 Hom.: 45 AF XY: 0.114 AC XY: 5985 AN XY: 52578

Gnomad AFR exome AF: 0.0986

Gnomad AMR exome AF: 0.132

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.0321

Gnomad SAS exome AF: 0.121

Gnomad FIN exome AF: 0.0841

Gnomad NFE exome AF: 0.119

Gnomad OTH exome AF: 0.123

GnomAD4 exome AF: 0.0862 AC: 106209 AN: 1232548 Hom.: 284 AF XY: 0.0862 AC XY: 52636 AN XY: 610506

Gnomad4 AFR exome AF: 0.0813

Gnomad4 AMR exome AF: 0.123

Gnomad4 ASJ exome AF: 0.0925

Gnomad4 EAS exome AF: 0.0282

Gnomad4 SAS exome AF: 0.0932

Gnomad4 FIN exome AF: 0.0637

Gnomad4 NFE exome AF: 0.0873

Gnomad4 OTH exome AF: 0.0914

GnomAD4 genome AF: 0.0618 AC: 7861 AN: 127212 Hom.: 223 Cov.: 0 AF XY: 0.0624 AC XY: 3815 AN XY: 61134

Gnomad4 AFR AF: 0.0529

Gnomad4 AMR AF: 0.0948

Gnomad4 ASJ AF: 0.0589

Gnomad4 EAS AF: 0.000950

Gnomad4 SAS AF: 0.0521

Gnomad4 FIN AF: 0.0571

Gnomad4 NFE AF: 0.0659

Gnomad4 OTH AF: 0.0656

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 07, 2014	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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 24, 2017	- -

Breast neoplasm Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 19, 2019

- -

Computational scores

Source: dbNSFP v4.3

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: rs56130510; hg19: chr2-215657182;