2-214780821-C-G

Variant names:

• chr2-214780821-C-G
• rs2070096
• NM_000465.4:c.1053G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000465.4(BARD1):​c.1053G>C​(p.Thr351Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 1,613,832 control chromosomes in the GnomAD database, including 37,931 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T351T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.20 (3045 hom., cov: 32)
  • Exomes 𝑓: 0.22 (34886 hom.)
• Consequence: BARD1 NM_000465.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13 O:1
• Conservation: PhyloP100: -1.32
• Publications: 37 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-214780821-C-G is Benign according to our data. Variant chr2-214780821-C-G is described in ClinVar as Benign. ClinVar VariationId is 142025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.32 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.222 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.1053G>C	p.Thr351Thr	synonymous	Exon 4 of 11	NP_000456.2	Q99728-1
	BARD1	NM_001282543.2		c.996G>C	p.Thr332Thr	synonymous	Exon 3 of 10	NP_001269472.1	Q99728-2
	BARD1	NM_001282545.2		c.215+16240G>C		intron	N/A	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.1053G>C	p.Thr351Thr	synonymous	Exon 4 of 11	ENSP00000260947.4	Q99728-1
	BARD1	ENST00000617164.5	TSL:1	c.996G>C	p.Thr332Thr	synonymous	Exon 3 of 10	ENSP00000480470.1	Q99728-2
	BARD1	ENST00000613706.5	TSL:1	c.906+147G>C		intron	N/A	ENSP00000484976.2	A0A087X2H0

Frequencies

GnomAD3 genomes AF: 0.197 AC: 29977 AN: 151940 Hom.: 3046 Cov.: 32

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.159

Gnomad SAS AF: 0.235

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.204

GnomAD2 exomes AF: 0.206 AC: 51790 AN: 251246 AF XY: 0.209

Gnomad AFR exome AF: 0.162

Gnomad AMR exome AF: 0.230

Gnomad ASJ exome AF: 0.243

Gnomad EAS exome AF: 0.162

Gnomad FIN exome AF: 0.129

Gnomad NFE exome AF: 0.214

Gnomad OTH exome AF: 0.214

GnomAD4 exome AF: 0.216 AC: 316117 AN: 1461774 Hom.: 34886 Cov.: 37 AF XY: 0.217 AC XY: 157658 AN XY: 727180

African (AFR) AF: 0.162 AC: 5436 AN: 33480

American (AMR) AF: 0.228 AC: 10183 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.245 AC: 6400 AN: 26134

East Asian (EAS) AF: 0.169 AC: 6698 AN: 39690

South Asian (SAS) AF: 0.239 AC: 20584 AN: 86256

European-Finnish (FIN) AF: 0.132 AC: 7041 AN: 53396

Middle Eastern (MID) AF: 0.206 AC: 1191 AN: 5768

European-Non Finnish (NFE) AF: 0.221 AC: 245964 AN: 1111956

Other (OTH) AF: 0.209 AC: 12620 AN: 60382

GnomAD4 genome AF: 0.197 AC: 29979 AN: 152058 Hom.: 3045 Cov.: 32 AF XY: 0.194 AC XY: 14407 AN XY: 74332

African (AFR) AF: 0.166 AC: 6889 AN: 41490

American (AMR) AF: 0.214 AC: 3274 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 835 AN: 3468

East Asian (EAS) AF: 0.160 AC: 825 AN: 5162

South Asian (SAS) AF: 0.233 AC: 1125 AN: 4822

European-Finnish (FIN) AF: 0.140 AC: 1481 AN: 10554

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.219 AC: 14894 AN: 67976

Other (OTH) AF: 0.202 AC: 427 AN: 2116

Alfa AF: 0.212 Hom.: 1121

Bravo AF: 0.201

Asia WGS AF: 0.194 AC: 675 AN: 3478

EpiCase AF: 0.227

EpiControl AF: 0.230

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Familial cancer of breast (5)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	2	not provided (3)
-	-	2	not specified (2)
-	-	1	Hereditary breast ovarian cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.17
DANN	Benign	0.30
PhyloP100		-1.3
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: rs2070096; hg19: chr2-215645545; COSMIC: COSV53608946; COSMIC: COSV53608946;