2-214752454-C-G

Variant names:

• chr2-214752454-C-G
• rs28997576
• NM_000465.4:c.1670G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000465.4(BARD1):​c.1670G>C​(p.Cys557Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0206 in 1,606,188 control chromosomes in the GnomAD database, including 419 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. C557F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.014 (12 hom., cov: 32)
  • Exomes 𝑓: 0.021 (407 hom.)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18 O:1
• Conservation: PhyloP100: 0.582
• Publications: 73 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=0.0048691034).
• BP6: Variant 2-214752454-C-G is Benign according to our data. Variant chr2-214752454-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 8045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0142 (2159/152264) while in subpopulation NFE AF = 0.0231 (1569/68026). AF 95% confidence interval is 0.0221. There are 12 homozygotes in GnomAd4. There are 994 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2159 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.1670G>C	p.Cys557Ser	missense	Exon 7 of 11	NP_000456.2	Q99728-1
	BARD1	NM_001282543.2		c.1613G>C	p.Cys538Ser	missense	Exon 6 of 10	NP_001269472.1	Q99728-2
	BARD1	NM_001282545.2		c.317G>C	p.Cys106Ser	missense	Exon 3 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.1670G>C	p.Cys557Ser	missense	Exon 7 of 11	ENSP00000260947.4	Q99728-1
	BARD1	ENST00000617164.5	TSL:1	c.1613G>C	p.Cys538Ser	missense	Exon 6 of 10	ENSP00000480470.1	Q99728-2
	BARD1	ENST00000613706.5	TSL:1	c.1262G>C	p.Cys421Ser	missense	Exon 7 of 11	ENSP00000484976.2	A0A087X2H0

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2158 AN: 152146 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00365

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.0231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00974

Gnomad FIN AF: 0.00868

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0230

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.0152 AC: 3811 AN: 251258 AF XY: 0.0158

Gnomad AFR exome AF: 0.00295

Gnomad AMR exome AF: 0.00585

Gnomad ASJ exome AF: 0.0237

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00963

Gnomad NFE exome AF: 0.0231

Gnomad OTH exome AF: 0.0137

GnomAD4 exome AF: 0.0213 AC: 30939 AN: 1453924 Hom.: 407 Cov.: 30 AF XY: 0.0212 AC XY: 15368 AN XY: 723714

African (AFR) AF: 0.00318 AC: 106 AN: 33290

American (AMR) AF: 0.00602 AC: 269 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.0230 AC: 601 AN: 26090

East Asian (EAS) AF: 0.0000758 AC: 3 AN: 39596

South Asian (SAS) AF: 0.0127 AC: 1093 AN: 86096

European-Finnish (FIN) AF: 0.0102 AC: 544 AN: 53340

Middle Eastern (MID) AF: 0.0267 AC: 153 AN: 5738

European-Non Finnish (NFE) AF: 0.0245 AC: 27102 AN: 1104986

Other (OTH) AF: 0.0178 AC: 1068 AN: 60094

GnomAD4 genome AF: 0.0142 AC: 2159 AN: 152264 Hom.: 12 Cov.: 32 AF XY: 0.0134 AC XY: 994 AN XY: 74446

African (AFR) AF: 0.00364 AC: 151 AN: 41540

American (AMR) AF: 0.0106 AC: 162 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0231 AC: 80 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00975 AC: 47 AN: 4822

European-Finnish (FIN) AF: 0.00868 AC: 92 AN: 10598

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0231 AC: 1569 AN: 68026

Other (OTH) AF: 0.0118 AC: 25 AN: 2110

Alfa AF: 0.0200 Hom.: 35

Bravo AF: 0.0136

TwinsUK AF: 0.0316 AC: 117

ALSPAC AF: 0.0249 AC: 96

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.0238 AC: 205

ExAC AF: 0.0156 AC: 1893

Asia WGS AF: 0.00347 AC: 12 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	8.0
DANN	Benign	0.39
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.58
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.14
Sift	Benign	0.30	T
Sift4G	Benign	0.12	T
Polyphen		0.040	B
Vest4		0.37
MutPred		0.13		Gain of phosphorylation at C557 (P = 0.0273)
MPC		0.093
ClinPred		0.011	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.067
gMVP		0.27
Mutation Taster		=97/3	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: rs28997576; hg19: chr2-215617178;