2-214792458-TAAAAA-TAAAAAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000465.4(BARD1):​c.216-14dupT 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 0.0039 (2 hom., cov: 0)
  • Exomes 𝑓: 0.020 (0 hom.)
• Consequence: BARD1 NM_000465.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• 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-T-TA is Benign according to our data. Variant chr2-214792458-T-TA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 502 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.216-14dupT		intron	N/A	NP_000456.2
	BARD1	NM_001282543.2		c.159-14dupT		intron	N/A	NP_001269472.1
	BARD1	NM_001282545.2		c.215+4602dupT		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_216-13insT		intron	N/A	ENSP00000260947.4
	BARD1	ENST00000617164.5	TSL:1	c.159-14_159-13insT		intron	N/A	ENSP00000480470.1
	BARD1	ENST00000613706.5	TSL:1	c.216-14_216-13insT		intron	N/A	ENSP00000484976.2

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

GnomAD2 exomes AF: 0.0148 AC: 1425 AN: 96390 AF XY: 0.0143

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 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

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

African (AFR) AF: 0.0270 AC: 713 AN: 26374

American (AMR) AF: 0.0156 AC: 374 AN: 23974

Ashkenazi Jewish (ASJ) AF: 0.0165 AC: 363 AN: 21950

East Asian (EAS) AF: 0.0288 AC: 945 AN: 32806

South Asian (SAS) AF: 0.0165 AC: 1110 AN: 67354

European-Finnish (FIN) AF: 0.0237 AC: 899 AN: 37940

Middle Eastern (MID) AF: 0.0130 AC: 53 AN: 4090

European-Non Finnish (NFE) AF: 0.0203 AC: 19972 AN: 983896

Other (OTH) AF: 0.0207 AC: 1072 AN: 51672

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

African (AFR) AF: 0.00752 AC: 259 AN: 34446

American (AMR) AF: 0.00176 AC: 23 AN: 13040

Ashkenazi Jewish (ASJ) AF: 0.000650 AC: 2 AN: 3076

East Asian (EAS) AF: 0.00950 AC: 40 AN: 4212

South Asian (SAS) AF: 0.00268 AC: 11 AN: 4104

European-Finnish (FIN) AF: 0.00778 AC: 51 AN: 6552

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

European-Non Finnish (NFE) AF: 0.00190 AC: 112 AN: 59072

Other (OTH) AF: 0.00228 AC: 4 AN: 1754

Alfa AF: 0.000533 Hom.: 67

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Familial cancer of breast (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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

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;