chr2-214728509-T-C

Variant names:

• chr2-214728509-T-C
• rs5020511
• ENST00000471590.5:n.836A>G

Variant summary

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

The ENST00000471590.5(BARD1):​n.836A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.608 in 674,652 control chromosomes in the GnomAD database, including 127,329 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 0.65 (31816 hom., cov: 28)
  • Exomes 𝑓: 0.60 (95513 hom.)
• Consequence: BARD1 ENST00000471590.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.48
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.764 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BARD1	NM_000465.4	c.*167A>G		3_prime_UTR_variant	Exon 11 of 11	ENST00000260947.9	NP_000456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9	c.*167A>G		3_prime_UTR_variant	Exon 11 of 11	1	NM_000465.4	ENSP00000260947.4

Frequencies

GnomAD3 genomes AF: 0.645 AC: 96663 AN: 149756 Hom.: 31782 Cov.: 28

Gnomad AFR AF: 0.770

Gnomad AMI AF: 0.619

Gnomad AMR AF: 0.546

Gnomad ASJ AF: 0.560

Gnomad EAS AF: 0.444

Gnomad SAS AF: 0.582

Gnomad FIN AF: 0.688

Gnomad MID AF: 0.545

Gnomad NFE AF: 0.612

Gnomad OTH AF: 0.605

GnomAD4 exome AF: 0.598 AC: 313693 AN: 524820 Hom.: 95513 Cov.: 7 AF XY: 0.596 AC XY: 163425 AN XY: 274258

African (AFR) AF: 0.767 AC: 10586 AN: 13796

American (AMR) AF: 0.494 AC: 8991 AN: 18190

Ashkenazi Jewish (ASJ) AF: 0.555 AC: 7933 AN: 14282

East Asian (EAS) AF: 0.443 AC: 13736 AN: 31022

South Asian (SAS) AF: 0.565 AC: 25200 AN: 44610

European-Finnish (FIN) AF: 0.674 AC: 18901 AN: 28060

Middle Eastern (MID) AF: 0.524 AC: 1268 AN: 2418

European-Non Finnish (NFE) AF: 0.611 AC: 210163 AN: 344162

Other (OTH) AF: 0.598 AC: 16915 AN: 28280

GnomAD4 genome AF: 0.646 AC: 96738 AN: 149832 Hom.: 31816 Cov.: 28 AF XY: 0.644 AC XY: 47035 AN XY: 72990

African (AFR) AF: 0.771 AC: 31553 AN: 40942

American (AMR) AF: 0.545 AC: 8163 AN: 14986

Ashkenazi Jewish (ASJ) AF: 0.560 AC: 1934 AN: 3456

East Asian (EAS) AF: 0.444 AC: 2246 AN: 5056

South Asian (SAS) AF: 0.583 AC: 2772 AN: 4756

European-Finnish (FIN) AF: 0.688 AC: 6674 AN: 9706

Middle Eastern (MID) AF: 0.555 AC: 161 AN: 290

European-Non Finnish (NFE) AF: 0.612 AC: 41417 AN: 67664

Other (OTH) AF: 0.607 AC: 1255 AN: 2066

Alfa AF: 0.631 Hom.: 6641

Bravo AF: 0.633

Asia WGS AF: 0.525 AC: 1824 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.8
DANN	Benign	0.85
PhyloP100		-1.5
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: rs5020511; hg19: chr2-215593233;