2-214725858-C-T

Variant names:

• chr2-214725858-C-T
• rs280621
• NM_000465.4:c.*2818G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000465.4(BARD1):​c.*2818G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.902 in 222,160 control chromosomes in the GnomAD database, including 90,403 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.91 (62678 hom., cov: 30)
  • Exomes 𝑓: 0.89 (27725 hom.)
• Consequence: BARD1 NM_000465.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.132
• Publications: 10 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.909 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.*2818G>A		3_prime_UTR	Exon 11 of 11	NP_000456.2	Q99728-1
	BARD1	NM_001282543.2		c.*2818G>A		3_prime_UTR	Exon 10 of 10	NP_001269472.1	Q99728-2
	BARD1	NM_001282545.2		c.*2818G>A		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.*2818G>A		3_prime_UTR	Exon 11 of 11	ENSP00000260947.4	Q99728-1

Frequencies

GnomAD3 genomes AF: 0.908 AC: 137916 AN: 151966 Hom.: 62618 Cov.: 30

Gnomad AFR AF: 0.890

Gnomad AMI AF: 0.925

Gnomad AMR AF: 0.912

Gnomad ASJ AF: 0.890

Gnomad EAS AF: 0.914

Gnomad SAS AF: 0.931

Gnomad FIN AF: 0.968

Gnomad MID AF: 0.835

Gnomad NFE AF: 0.907

Gnomad OTH AF: 0.893

GnomAD4 exome AF: 0.889 AC: 62291 AN: 70076 Hom.: 27725 Cov.: 0 AF XY: 0.888 AC XY: 28731 AN XY: 32360

African (AFR) AF: 0.895 AC: 2996 AN: 3348

American (AMR) AF: 0.903 AC: 1935 AN: 2144

Ashkenazi Jewish (ASJ) AF: 0.887 AC: 3880 AN: 4374

East Asian (EAS) AF: 0.838 AC: 8521 AN: 10168

South Asian (SAS) AF: 0.932 AC: 572 AN: 614

European-Finnish (FIN) AF: 0.978 AC: 45 AN: 46

Middle Eastern (MID) AF: 0.830 AC: 357 AN: 430

European-Non Finnish (NFE) AF: 0.900 AC: 38780 AN: 43076

Other (OTH) AF: 0.886 AC: 5205 AN: 5876

GnomAD4 genome AF: 0.908 AC: 138035 AN: 152084 Hom.: 62678 Cov.: 30 AF XY: 0.912 AC XY: 67800 AN XY: 74360

African (AFR) AF: 0.890 AC: 36908 AN: 41458

American (AMR) AF: 0.912 AC: 13938 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.890 AC: 3090 AN: 3470

East Asian (EAS) AF: 0.914 AC: 4722 AN: 5168

South Asian (SAS) AF: 0.931 AC: 4496 AN: 4828

European-Finnish (FIN) AF: 0.968 AC: 10247 AN: 10584

Middle Eastern (MID) AF: 0.827 AC: 243 AN: 294

European-Non Finnish (NFE) AF: 0.907 AC: 61662 AN: 67980

Other (OTH) AF: 0.894 AC: 1887 AN: 2110

Alfa AF: 0.902 Hom.: 106974

Bravo AF: 0.902

Asia WGS AF: 0.921 AC: 3204 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	2.3
DANN	Benign	0.35
PhyloP100		0.13
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: rs280621; hg19: chr2-215590582;