2-214792457-T-G

Variant names:

• chr2-214792457-T-G
• rs199846428
• NM_000465.4:c.216-12A>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BS2_Supporting

The NM_000465.4(BARD1):​c.216-12A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000413 in 1,453,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0000087 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: BARD1 NM_000465.4 intron
• Scores: Splicing: ADA: 0.00003918
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.528
• Publications: 0 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-214792457-T-G is Benign according to our data. Variant chr2-214792457-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 377551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BARD1	NM_000465.4	MANE Select	c.216-12A>C		intron	N/A	NP_000456.2
	BARD1	NM_001282543.2		c.159-12A>C		intron	N/A	NP_001269472.1
	BARD1	NM_001282545.2		c.215+4604A>C		intron	N/A	NP_001269474.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BARD1	ENST00000260947.9	TSL:1 MANE Select	c.216-12A>C		intron	N/A	ENSP00000260947.4
	BARD1	ENST00000617164.5	TSL:1	c.159-12A>C		intron	N/A	ENSP00000480470.1
	BARD1	ENST00000613706.5	TSL:1	c.216-12A>C		intron	N/A	ENSP00000484976.2

Frequencies

GnomAD3 genomes AF: 0.00000873 AC: 1 AN: 114606 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000363

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000217 AC: 2 AN: 92048 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000187

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000245

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000373 AC: 5 AN: 1338918 Hom.: 0 Cov.: 33 AF XY: 0.00000453 AC XY: 3 AN XY: 662078

African (AFR) AF: 0.00 AC: 0 AN: 27640

American (AMR) AF: 0.00 AC: 0 AN: 26878

Ashkenazi Jewish (ASJ) AF: 0.000174 AC: 4 AN: 23054

East Asian (EAS) AF: 0.00 AC: 0 AN: 33262

South Asian (SAS) AF: 0.00 AC: 0 AN: 69288

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39734

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4454

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1059662

Other (OTH) AF: 0.0000182 AC: 1 AN: 54946

GnomAD4 genome AF: 0.00000873 AC: 1 AN: 114606 Hom.: 0 Cov.: 29 AF XY: 0.0000181 AC XY: 1 AN XY: 55272

African (AFR) AF: 0.00 AC: 0 AN: 30354

American (AMR) AF: 0.00 AC: 0 AN: 10602

Ashkenazi Jewish (ASJ) AF: 0.000363 AC: 1 AN: 2758

East Asian (EAS) AF: 0.00 AC: 0 AN: 4400

South Asian (SAS) AF: 0.00 AC: 0 AN: 3502

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7052

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53436

Other (OTH) AF: 0.00 AC: 0 AN: 1520

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Familial cancer of breast (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.4
DANN	Benign	0.62
PhyloP100		-0.53
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000039
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.010		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: rs199846428; hg19: chr2-215657181;