2-214792458-TAAAAA-TAAA

Variant names:

• chr2-214792458-TAA-T
• rs56130510
• NM_000465.4:c.216-15_216-14delTT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_000465.4(BARD1):​c.216-15_216-14delTT variant causes a 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 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.804
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• breast cancer

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• familial ovarian cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 334196.
• 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 rank	MANE	Protein	UniProt
BARD1	NM_000465.4	c.216-15_216-14delTT		intron_variant	Intron 2 of 10	ENST00000260947.9	NP_000456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9	c.216-15_216-14delTT		intron_variant	Intron 2 of 10	1	NM_000465.4	ENSP00000260947.4

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

GnomAD2 exomes AF: 0.111 AC: 10714 AN: 96390 AF XY: 0.114

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0813 AC: 2114 AN: 26000

American (AMR) AF: 0.123 AC: 2884 AN: 23466

Ashkenazi Jewish (ASJ) AF: 0.0925 AC: 1988 AN: 21498

East Asian (EAS) AF: 0.0282 AC: 911 AN: 32314

South Asian (SAS) AF: 0.0932 AC: 6151 AN: 66018

European-Finnish (FIN) AF: 0.0637 AC: 2380 AN: 37360

Middle Eastern (MID) AF: 0.100 AC: 404 AN: 4026

European-Non Finnish (NFE) AF: 0.0873 AC: 84743 AN: 971146

Other (OTH) AF: 0.0914 AC: 4634 AN: 50720

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.0529 AC: 1823 AN: 34446

American (AMR) AF: 0.0948 AC: 1236 AN: 13032

Ashkenazi Jewish (ASJ) AF: 0.0589 AC: 181 AN: 3074

East Asian (EAS) AF: 0.000950 AC: 4 AN: 4212

South Asian (SAS) AF: 0.0521 AC: 214 AN: 4104

European-Finnish (FIN) AF: 0.0571 AC: 373 AN: 6536

Middle Eastern (MID) AF: 0.0720 AC: 17 AN: 236

European-Non Finnish (NFE) AF: 0.0659 AC: 3892 AN: 59052

Other (OTH) AF: 0.0656 AC: 115 AN: 1754

Alfa AF: 0.0333 Hom.: 67

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

Nov 07, 2014

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 24, 2017

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast neoplasm Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Aug 19, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.80
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs56130510; hg19: chr2-215657182;