2-214792458-TAAAA-TAAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000465.4(BARD1):c.216-14del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (5418 hom., cov: 0)
  • Exomes 𝑓: 0.40 (2229 hom.)
  • Failed GnomAD Quality Control
• Consequence: BARD1 NM_000465.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.884

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 -16 ACMG points.

• BP6: Variant 2-214792458-TA-T is Benign according to our data. Variant chr2-214792458-TA-T is described in ClinVar as [Likely_benign]. Clinvar id is 142007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-214792458-TA-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.316 AC: 40170 AN: 127116 Hom.: 5420 Cov.: 0

Gnomad AFR AF: 0.327

Gnomad AMI AF: 0.344

Gnomad AMR AF: 0.338

Gnomad ASJ AF: 0.337

Gnomad EAS AF: 0.239

Gnomad SAS AF: 0.358

Gnomad FIN AF: 0.199

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.319

Gnomad OTH AF: 0.333

GnomAD3 exomes AF: 0.423 AC: 40761 AN: 96390 Hom.: 258 AF XY: 0.423 AC XY: 22234 AN XY: 52578

Gnomad AFR exome AF: 0.426

Gnomad AMR exome AF: 0.416

Gnomad ASJ exome AF: 0.431

Gnomad EAS exome AF: 0.451

Gnomad SAS exome AF: 0.434

Gnomad FIN exome AF: 0.403

Gnomad NFE exome AF: 0.418

Gnomad OTH exome AF: 0.425

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.403 AC: 468747 AN: 1161964 Hom.: 2229 Cov.: 0 AF XY: 0.405 AC XY: 233202 AN XY: 575634

Gnomad4 AFR exome AF: 0.406

Gnomad4 AMR exome AF: 0.388

Gnomad4 ASJ exome AF: 0.413

Gnomad4 EAS exome AF: 0.435

Gnomad4 SAS exome AF: 0.416

Gnomad4 FIN exome AF: 0.359

Gnomad4 NFE exome AF: 0.403

Gnomad4 OTH exome AF: 0.403

GnomAD4 genome AF: 0.316 AC: 40170 AN: 127148 Hom.: 5418 Cov.: 0 AF XY: 0.312 AC XY: 19090 AN XY: 61092

Gnomad4 AFR AF: 0.326

Gnomad4 AMR AF: 0.338

Gnomad4 ASJ AF: 0.337

Gnomad4 EAS AF: 0.239

Gnomad4 SAS AF: 0.358

Gnomad4 FIN AF: 0.199

Gnomad4 NFE AF: 0.319

Gnomad4 OTH AF: 0.330

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 31, 2014	The variant is found in BR-OV-HEREDIC panel(s). -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 07, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 11, 2013	Internal frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

Breast neoplasm Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BARD1 c.216-14delT variant was not identified in the literature nor was it identified in the Cosmic, MutDB, Zhejiang Colon Cancer Database, NHLBI Exome Sequencing Project databases. The variant was identified in dbSNP (ID: rs56130510) as “With Likely benign allele”, ClinVar (classified benign by Ambry Genetics and GeneDx; and likely benign by Illumina), Clinvitae (2x), and in the 1000 Genomes Project at a frequency of 5%, as well as in HAPMAP-SAS in 488 of 978 chromosomes (frequency: 0.5)/-AMR in 334 of 694 chromosomes (frequency: 0.5)/-EUR in 442 of 1006 chromosomes (frequency: 0.4), and the Exome Aggregation Consortium (August 8th 2016) control database in 1 of 976 chromosomes (frequency 0.001). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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;