2-214781265-T-G

Variant names:

• chr2-214781265-T-G
• rs28997574
• NM_000465.4:c.609A>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000465.4(BARD1):​c.609A>C​(p.Gly203Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00947 in 1,596,334 control chromosomes in the GnomAD database, including 118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G203G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.010 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0094 (108 hom.)
• Consequence: BARD1 NM_000465.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -0.137
• Publications: 10 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=-0.86).
• BP6: Variant 2-214781265-T-G is Benign according to our data. Variant chr2-214781265-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.137 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00998 (1520/152274) while in subpopulation AMR AF = 0.0152 (232/15282). AF 95% confidence interval is 0.0136. There are 10 homozygotes in GnomAd4. There are 718 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1520 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.609A>C	p.Gly203Gly	synonymous	Exon 4 of 11	NP_000456.2	Q99728-1
	BARD1	NM_001282543.2		c.552A>C	p.Gly184Gly	synonymous	Exon 3 of 10	NP_001269472.1	Q99728-2
	BARD1	NM_001282545.2		c.215+15796A>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.609A>C	p.Gly203Gly	synonymous	Exon 4 of 11	ENSP00000260947.4	Q99728-1
	BARD1	ENST00000617164.5	TSL:1	c.552A>C	p.Gly184Gly	synonymous	Exon 3 of 10	ENSP00000480470.1	Q99728-2
	BARD1	ENST00000613706.5	TSL:1	c.609A>C	p.Gly203Gly	synonymous	Exon 4 of 11	ENSP00000484976.2	A0A087X2H0

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1522 AN: 152156 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00994

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0152

Gnomad ASJ AF: 0.0265

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0100

Gnomad OTH AF: 0.0254

GnomAD2 exomes AF: 0.00890 AC: 2080 AN: 233788 AF XY: 0.00877

Gnomad AFR exome AF: 0.00917

Gnomad AMR exome AF: 0.0136

Gnomad ASJ exome AF: 0.0294

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000800

Gnomad NFE exome AF: 0.00974

Gnomad OTH exome AF: 0.0184

GnomAD4 exome AF: 0.00942 AC: 13596 AN: 1444060 Hom.: 108 Cov.: 34 AF XY: 0.00933 AC XY: 6693 AN XY: 717598

African (AFR) AF: 0.0120 AC: 385 AN: 32066

American (AMR) AF: 0.0144 AC: 575 AN: 39794

Ashkenazi Jewish (ASJ) AF: 0.0298 AC: 754 AN: 25280

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.00298 AC: 242 AN: 81266

European-Finnish (FIN) AF: 0.000979 AC: 52 AN: 53142

Middle Eastern (MID) AF: 0.0480 AC: 271 AN: 5650

European-Non Finnish (NFE) AF: 0.00951 AC: 10536 AN: 1107682

Other (OTH) AF: 0.0131 AC: 781 AN: 59558

GnomAD4 genome AF: 0.00998 AC: 1520 AN: 152274 Hom.: 10 Cov.: 32 AF XY: 0.00964 AC XY: 718 AN XY: 74460

African (AFR) AF: 0.00993 AC: 413 AN: 41572

American (AMR) AF: 0.0152 AC: 232 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0265 AC: 92 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4824

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10612

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0100 AC: 680 AN: 68024

Other (OTH) AF: 0.0251 AC: 53 AN: 2110

Alfa AF: 0.00978 Hom.: 18

Bravo AF: 0.0113

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0122

EpiControl AF: 0.0136

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Familial cancer of breast (6)
-	-	4	not specified (4)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	not provided (3)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.96
DANN	Benign	0.43
PhyloP100		-0.14
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=95/5	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: rs28997574; hg19: chr2-215645989;