chr2-214728360-A-G

Variant names:

• chr2-214728360-A-G
• rs59457185
• NM_000465.4:c.*316T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000465.4(BARD1):​c.*316T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00307 in 332,816 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0057 (9 hom., cov: 31)
  • Exomes 𝑓: 0.00083 (1 hom.)
• Consequence: BARD1 NM_000465.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.46
• Publications: 1 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):

• BARD1-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• breast cancer

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

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

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-214728360-A-G is Benign according to our data. Variant chr2-214728360-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1712140.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00575 (872/151658) while in subpopulation AFR AF = 0.0194 (803/41416). AF 95% confidence interval is 0.0183. There are 9 homozygotes in GnomAd4. There are 444 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 872 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.*316T>C		3_prime_UTR	Exon 11 of 11	NP_000456.2	Q99728-1
	BARD1	NM_001282543.2		c.*316T>C		3_prime_UTR	Exon 10 of 10	NP_001269472.1	Q99728-2
	BARD1	NM_001282545.2		c.*316T>C		3_prime_UTR	Exon 7 of 7	NP_001269474.1	C9IYG1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BARD1	ENST00000260947.9	TSL:1 MANE Select	c.*316T>C		3_prime_UTR	Exon 11 of 11	ENSP00000260947.4	Q99728-1
	BARD1	ENST00000915563.1		c.*316T>C		3_prime_UTR	Exon 9 of 9	ENSP00000585622.1
	BARD1	ENST00000617164.5	TSL:1	c.*316T>C		downstream_gene	N/A	ENSP00000480470.1	Q99728-2

Frequencies

GnomAD3 genomes AF: 0.00572 AC: 867 AN: 151570 Hom.: 9 Cov.: 31

Gnomad AFR AF: 0.0193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00362

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00624

GnomAD4 exome AF: 0.000834 AC: 151 AN: 181158 Hom.: 1 Cov.: 0 AF XY: 0.000684 AC XY: 62 AN XY: 90624

African (AFR) AF: 0.0196 AC: 119 AN: 6068

American (AMR) AF: 0.00160 AC: 11 AN: 6872

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7560

East Asian (EAS) AF: 0.00 AC: 0 AN: 15274

South Asian (SAS) AF: 0.000138 AC: 2 AN: 14454

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5488

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 886

European-Non Finnish (NFE) AF: 0.0000178 AC: 2 AN: 112386

Other (OTH) AF: 0.00140 AC: 17 AN: 12170

GnomAD4 genome AF: 0.00575 AC: 872 AN: 151658 Hom.: 9 Cov.: 31 AF XY: 0.00599 AC XY: 444 AN XY: 74114

African (AFR) AF: 0.0194 AC: 803 AN: 41416

American (AMR) AF: 0.00361 AC: 55 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67894

Other (OTH) AF: 0.00618 AC: 13 AN: 2102

Alfa AF: 0.00444 Hom.: 1

Bravo AF: 0.00665

Asia WGS AF: 0.00173 AC: 7 AN: 3472

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.8
DANN	Benign	0.84
PhyloP100		1.5
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: rs59457185; hg19: chr2-215593084;