2-214792458-TAAAAA-TAAAAAAA

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_000465.4(BARD1):​c.216-15_216-14dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000086 (1 hom., cov: 0)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: BARD1 NM_000465.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.884
• 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 2-214792458-T-TAA is Benign according to our data. Variant chr2-214792458-T-TAA is described in ClinVar as Likely_benign. ClinVar VariationId is 2575125.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 11 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000465.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BARD1	NM_000465.4	MANE Select	c.216-15_216-14dupTT		intron	N/A	NP_000456.2
	BARD1	NM_001282543.2		c.159-15_159-14dupTT		intron	N/A	NP_001269472.1
	BARD1	NM_001282545.2		c.215+4601_215+4602dupTT		intron	N/A	NP_001269474.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BARD1	ENST00000260947.9	TSL:1 MANE Select	c.216-14_216-13insTT		intron	N/A	ENSP00000260947.4
	BARD1	ENST00000617164.5	TSL:1	c.159-14_159-13insTT		intron	N/A	ENSP00000480470.1
	BARD1	ENST00000613706.5	TSL:1	c.216-14_216-13insTT		intron	N/A	ENSP00000484976.2

Frequencies

GnomAD3 genomes AF: 0.0000864 AC: 11 AN: 127246 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000485

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000152

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000249 AC: 24 AN: 96390 AF XY: 0.000285

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000411

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000150

Gnomad FIN exome AF: 0.000306

Gnomad NFE exome AF: 0.000277

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000135 AC: 172 AN: 1272380 Hom.: 0 Cov.: 0 AF XY: 0.000157 AC XY: 99 AN XY: 630136

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

African (AFR) AF: 0.000112 AC: 3 AN: 26806

American (AMR) AF: 0.000207 AC: 5 AN: 24182

Ashkenazi Jewish (ASJ) AF: 0.000135 AC: 3 AN: 22230

East Asian (EAS) AF: 0.000150 AC: 5 AN: 33368

South Asian (SAS) AF: 0.000264 AC: 18 AN: 68192

European-Finnish (FIN) AF: 0.000182 AC: 7 AN: 38400

Middle Eastern (MID) AF: 0.000241 AC: 1 AN: 4146

European-Non Finnish (NFE) AF: 0.000119 AC: 119 AN: 1002578

Other (OTH) AF: 0.000210 AC: 11 AN: 52478

⚠️ 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: 0.0000864 AC: 11 AN: 127276 Hom.: 1 Cov.: 0 AF XY: 0.0000818 AC XY: 5 AN XY: 61160

African (AFR) AF: 0.00 AC: 0 AN: 34454

American (AMR) AF: 0.00 AC: 0 AN: 13042

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3076

East Asian (EAS) AF: 0.00 AC: 0 AN: 4212

South Asian (SAS) AF: 0.000487 AC: 2 AN: 4104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.000152 AC: 9 AN: 59080

Other (OTH) AF: 0.00 AC: 0 AN: 1754

Alfa AF: 0.00 Hom.: 67

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.88
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs56130510; hg19: chr2-215657182;