2-214792458-TAAAA-TAAAAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000465.4(BARD1):c.216-14_216-13insT 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 0.0039 (2 hom., cov: 0)
  • Exomes 𝑓: 0.020 (0 hom.)
• Consequence: BARD1 NM_000465.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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-T-TA is Benign according to our data. Variant chr2-214792458-T-TA is described in ClinVar as [Likely_benign]. Clinvar id is 1198408.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00394 (502/127258) while in subpopulation EAS AF= 0.0095 (40/4212). AF 95% confidence interval is 0.00717. There are 2 homozygotes in gnomad4. There are 239 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd at 501 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BARD1	NM_000465.4	c.216-14_216-13insT		splice_polypyrimidine_tract_variant, intron_variant		ENST00000260947.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BARD1	ENST00000260947.9	c.216-14_216-13insT		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000465.4	P2

Frequencies

GnomAD3 genomes AF: 0.00394 AC: 501 AN: 127228 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.00750

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.000650

Gnomad EAS AF: 0.00947

Gnomad SAS AF: 0.00267

Gnomad FIN AF: 0.00778

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00190

Gnomad OTH AF: 0.00230

GnomAD3 exomes AF: 0.0148 AC: 1425 AN: 96390 Hom.: 0 AF XY: 0.0143 AC XY: 751 AN XY: 52578

Gnomad AFR exome AF: 0.0192

Gnomad AMR exome AF: 0.0168

Gnomad ASJ exome AF: 0.0117

Gnomad EAS exome AF: 0.0348

Gnomad SAS exome AF: 0.00874

Gnomad FIN exome AF: 0.0158

Gnomad NFE exome AF: 0.0129

Gnomad OTH exome AF: 0.0102

GnomAD4 exome AF: 0.0204 AC: 25501 AN: 1250056 Hom.: 0 Cov.: 0 AF XY: 0.0197 AC XY: 12220 AN XY: 619326

Gnomad4 AFR exome AF: 0.0270

Gnomad4 AMR exome AF: 0.0156

Gnomad4 ASJ exome AF: 0.0165

Gnomad4 EAS exome AF: 0.0288

Gnomad4 SAS exome AF: 0.0165

Gnomad4 FIN exome AF: 0.0237

Gnomad4 NFE exome AF: 0.0203

Gnomad4 OTH exome AF: 0.0207

GnomAD4 genome AF: 0.00394 AC: 502 AN: 127258 Hom.: 2 Cov.: 0 AF XY: 0.00391 AC XY: 239 AN XY: 61152

Gnomad4 AFR AF: 0.00752

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.000650

Gnomad4 EAS AF: 0.00950

Gnomad4 SAS AF: 0.00268

Gnomad4 FIN AF: 0.00778

Gnomad4 NFE AF: 0.00190

Gnomad4 OTH AF: 0.00228

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 19, 2019

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

May 27, 2020

- -

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;