rs2228456

Variant names:

• chr2-214730479-A-G
• rs2228456
• NM_000465.4:c.1933T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-214730479-A-G
• chr2-214730479-A-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000465.4(BARD1):​c.1933T>C​(p.Cys645Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00376 in 1,613,948 control chromosomes in the GnomAD database, including 198 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C645Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.020 (104 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (94 hom.)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 1.56
• Publications: 21 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00192523).
• BP6: Variant 2-214730479-A-G is Benign according to our data. Variant chr2-214730479-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 142135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0652 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.1933T>C	p.Cys645Arg	missense	Exon 10 of 11	NP_000456.2	Q99728-1
	BARD1	NM_001282543.2		c.1876T>C	p.Cys626Arg	missense	Exon 9 of 10	NP_001269472.1	Q99728-2
	BARD1	NM_001282545.2		c.580T>C	p.Cys194Arg	missense	Exon 6 of 7	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.1933T>C	p.Cys645Arg	missense	Exon 10 of 11	ENSP00000260947.4	Q99728-1
	BARD1	ENST00000617164.5	TSL:1	c.1876T>C	p.Cys626Arg	missense	Exon 9 of 10	ENSP00000480470.1	Q99728-2
	BARD1	ENST00000613706.5	TSL:1	c.1525T>C	p.Cys509Arg	missense	Exon 10 of 11	ENSP00000484976.2	A0A087X2H0

Frequencies

GnomAD3 genomes AF: 0.0197 AC: 2994 AN: 152116 Hom.: 104 Cov.: 32

Gnomad AFR AF: 0.0673

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00929

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0167

GnomAD2 exomes AF: 0.00523 AC: 1314 AN: 251364 AF XY: 0.00372

Gnomad AFR exome AF: 0.0702

Gnomad AMR exome AF: 0.00266

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000739

Gnomad NFE exome AF: 0.000246

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00210 AC: 3063 AN: 1461714 Hom.: 94 Cov.: 30 AF XY: 0.00181 AC XY: 1313 AN XY: 727150

African (AFR) AF: 0.0683 AC: 2286 AN: 33460

American (AMR) AF: 0.00313 AC: 140 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00241 AC: 63 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86254

European-Finnish (FIN) AF: 0.000543 AC: 29 AN: 53400

Middle Eastern (MID) AF: 0.00607 AC: 35 AN: 5766

European-Non Finnish (NFE) AF: 0.000164 AC: 182 AN: 1111938

Other (OTH) AF: 0.00525 AC: 317 AN: 60386

GnomAD4 genome AF: 0.0197 AC: 2999 AN: 152234 Hom.: 104 Cov.: 32 AF XY: 0.0190 AC XY: 1416 AN XY: 74442

African (AFR) AF: 0.0673 AC: 2793 AN: 41528

American (AMR) AF: 0.00928 AC: 142 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.000566 AC: 6 AN: 10608

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68010

Other (OTH) AF: 0.0166 AC: 35 AN: 2112

Alfa AF: 0.00634 Hom.: 80

Bravo AF: 0.0217

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0670 AC: 295

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00639 AC: 776

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	Familial cancer of breast (7)
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	14
DANN	Benign	0.70
DEOGEN2	Benign	0.077	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.35	N
PhyloP100		1.6
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.048
Sift	Benign	0.87	T
Sift4G	Benign	0.90	T
Polyphen		0.0010	B
Vest4		0.14
MVP		0.36
MPC		0.13
ClinPred		0.0027	T
GERP RS		4.6
PromoterAI		0.048	Neutral
Varity_R		0.25
gMVP		0.69
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs2228456; hg19: chr2-215595203;