2-214792458-TAAAAA-TAAAA

Variant names:

• chr2-214792458-TA-T
• rs56130510
• NM_000465.4:c.216-14delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000465.4(BARD1):​c.216-14delT 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 0.32 (5418 hom., cov: 0)
  • Exomes 𝑓: 0.40 (2229 hom.)
  • Failed GnomAD Quality Control
• Consequence: BARD1 NM_000465.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• 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: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 142007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

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.216-14delT		intron	N/A	NP_000456.2
	BARD1	NM_001282543.2		c.159-14delT		intron	N/A	NP_001269472.1
	BARD1	NM_001282545.2		c.215+4602delT		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.216-14delT		intron	N/A	ENSP00000260947.4
	BARD1	ENST00000617164.5	TSL:1	c.159-14delT		intron	N/A	ENSP00000480470.1
	BARD1	ENST00000613706.5	TSL:1	c.216-14delT		intron	N/A	ENSP00000484976.2

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

GnomAD2 exomes AF: 0.423 AC: 40761 AN: 96390 AF XY: 0.423

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 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

African (AFR) AF: 0.406 AC: 10026 AN: 24698

American (AMR) AF: 0.388 AC: 8943 AN: 23042

Ashkenazi Jewish (ASJ) AF: 0.413 AC: 8592 AN: 20820

East Asian (EAS) AF: 0.435 AC: 12991 AN: 29854

South Asian (SAS) AF: 0.416 AC: 26537 AN: 63722

European-Finnish (FIN) AF: 0.359 AC: 12697 AN: 35382

Middle Eastern (MID) AF: 0.383 AC: 1492 AN: 3894

European-Non Finnish (NFE) AF: 0.403 AC: 368045 AN: 912378

Other (OTH) AF: 0.403 AC: 19424 AN: 48174

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

African (AFR) AF: 0.326 AC: 11241 AN: 34432

American (AMR) AF: 0.338 AC: 4395 AN: 13018

Ashkenazi Jewish (ASJ) AF: 0.337 AC: 1035 AN: 3074

East Asian (EAS) AF: 0.239 AC: 1005 AN: 4206

South Asian (SAS) AF: 0.358 AC: 1468 AN: 4100

European-Finnish (FIN) AF: 0.199 AC: 1304 AN: 6550

Middle Eastern (MID) AF: 0.318 AC: 75 AN: 236

European-Non Finnish (NFE) AF: 0.319 AC: 18807 AN: 59018

Other (OTH) AF: 0.330 AC: 577 AN: 1750

Alfa AF: 0.0746 Hom.: 67

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	3	not specified (3)
-	-	2	Familial cancer of breast (2)
-	-	1	Breast neoplasm (1)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

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

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

Other links and lift over

dbSNP: rs56130510; hg19: chr2-215657182; COSMIC: COSV53618589; COSMIC: COSV53618589;