chr2-214781245-GTT-G

Variant names:

• chr2-214781245-GTT-G
• rs864622223
• NM_000465.4:c.627_628delAA

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 16P and 1B. PVS1 PP5_Very_Strong BS2_Supporting

The NM_000465.4(BARD1):​c.627_628delAA​(p.Lys209AsnfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000416 in 1,442,972 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. K209K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: BARD1 NM_000465.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 2.37
• Publications: 9 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: Pathogenic. The variant received 15 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-214781245-GTT-G is Pathogenic according to our data. Variant chr2-214781245-GTT-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 219726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 6 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.627_628delAA	p.Lys209AsnfsTer4	frameshift	Exon 4 of 11	NP_000456.2
	BARD1	NM_001282543.2		c.570_571delAA	p.Lys190AsnfsTer4	frameshift	Exon 3 of 10	NP_001269472.1
	BARD1	NR_104212.2		n.592_593delAA		non_coding_transcript_exon	Exon 3 of 10

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BARD1	ENST00000260947.9	TSL:1 MANE Select	c.627_628delAA	p.Lys209AsnfsTer4	frameshift	Exon 4 of 11	ENSP00000260947.4
	BARD1	ENST00000617164.5	TSL:1	c.570_571delAA	p.Lys190AsnfsTer4	frameshift	Exon 3 of 10	ENSP00000480470.1
	BARD1	ENST00000613706.5	TSL:1	c.627_628delAA	p.Lys209AsnfsTer4	frameshift	Exon 4 of 11	ENSP00000484976.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000429 AC: 1 AN: 233042 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000923

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000416 AC: 6 AN: 1442972 Hom.: 0 AF XY: 0.00000418 AC XY: 3 AN XY: 717132

African (AFR) AF: 0.00 AC: 0 AN: 32008

American (AMR) AF: 0.00 AC: 0 AN: 39364

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25230

East Asian (EAS) AF: 0.00 AC: 0 AN: 39582

South Asian (SAS) AF: 0.00 AC: 0 AN: 81130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53098

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5638

European-Non Finnish (NFE) AF: 0.00000542 AC: 6 AN: 1107412

Other (OTH) AF: 0.00 AC: 0 AN: 59510

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Familial cancer of breast (3)
2	-	-	BARD1-related cancer predisposition (2)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	Malignant tumor of breast (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.4
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs864622223; hg19: chr2-215645969;