chr2-214792394-C-T

Variant names:

• chr2-214792394-C-T
• rs756165637
• NM_000465.4:c.267G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_000465.4(BARD1):​c.267G>A​(p.Pro89Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,460,674 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P89P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: BARD1 NM_000465.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.0110
• Publications: 2 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 2-214792394-C-T is Benign according to our data. Variant chr2-214792394-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 184114.
• BP7: Synonymous conserved (PhyloP=-0.011 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 19 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.267G>A	p.Pro89Pro	synonymous	Exon 3 of 11	NP_000456.2
	BARD1	NM_001282543.2		c.210G>A	p.Pro70Pro	synonymous	Exon 2 of 10	NP_001269472.1
	BARD1	NM_001282549.2		c.267G>A	p.Pro89Pro	synonymous	Exon 3 of 5	NP_001269478.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BARD1	ENST00000260947.9	TSL:1 MANE Select	c.267G>A	p.Pro89Pro	synonymous	Exon 3 of 11	ENSP00000260947.4
	BARD1	ENST00000617164.5	TSL:1	c.210G>A	p.Pro70Pro	synonymous	Exon 2 of 10	ENSP00000480470.1
	BARD1	ENST00000613706.5	TSL:1	c.267G>A	p.Pro89Pro	synonymous	Exon 3 of 11	ENSP00000484976.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251030 AF XY: 0.0000221

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1460674 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 726612

African (AFR) AF: 0.0000299 AC: 1 AN: 33426

American (AMR) AF: 0.0000672 AC: 3 AN: 44624

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39594

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111442

Other (OTH) AF: 0.00 AC: 0 AN: 60312

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000547

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	8.2
DANN	Benign	0.62
PhyloP100		-0.011
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: rs756165637; hg19: chr2-215657118; COSMIC: COSV53610747; COSMIC: COSV53610747;