rs587780021

Variant names:

• chr2-214745842-G-A
• rs587780021
• NM_000465.4:c.1690C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-214745842-G-A
• chr2-214745842-G-C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 20P and 4B. PVS1 PS3 PP5_Very_Strong BS2

The NM_000465.4(BARD1):​c.1690C>T​(p.Gln564*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000248 in 1,613,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002762790: PS3, PS4_STR *Note: Since the input directly mentions PS3, it is treated as providing evidence for PS3 without needing to extract a specific snippet.* However, based on the instructions and examples provided, the correct response should be: **Output**: `no`" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q564Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: BARD1 NM_000465.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:30
• Conservation: PhyloP100: 4.84
• Publications: 38 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: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV002762790: PS3, PS4_STR *Note: Since the input directly mentions PS3, it is treated as providing evidence for PS3 without needing to extract a specific snippet.* However, based on the instructions and examples provided, the correct response should be: **Output**: `no`; SCV000149525: Published functional studies demonstrate a damaging effect: significantly reduced homology-directed repair and may result in abnormal splicing (Ratajska 2015, Adamovich 2019)
• PP5: Variant 2-214745842-G-A is Pathogenic according to our data. Variant chr2-214745842-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 127720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 36 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.1690C>T	p.Gln564*	stop_gained	Exon 8 of 11	NP_000456.2	Q99728-1
	BARD1	NM_001282543.2		c.1633C>T	p.Gln545*	stop_gained	Exon 7 of 10	NP_001269472.1	Q99728-2
	BARD1	NM_001282545.2		c.337C>T	p.Gln113*	stop_gained	Exon 4 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.1690C>T	p.Gln564*	stop_gained	Exon 8 of 11	ENSP00000260947.4	Q99728-1
	BARD1	ENST00000617164.5	TSL:1	c.1633C>T	p.Gln545*	stop_gained	Exon 7 of 10	ENSP00000480470.1	Q99728-2
	BARD1	ENST00000613706.5	TSL:1	c.1282C>T	p.Gln428*	stop_gained	Exon 8 of 11	ENSP00000484976.2	A0A087X2H0

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152092 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251300 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1461732 Hom.: 0 Cov.: 31 AF XY: 0.0000234 AC XY: 17 AN XY: 727168

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.0000306 AC: 34 AN: 1111954

Other (OTH) AF: 0.0000166 AC: 1 AN: 60386

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152092 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74282

African (AFR) AF: 0.00 AC: 0 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000347 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000494 AC: 6

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
10	-	-	not provided (10)
9	-	-	Familial cancer of breast (9)
4	-	-	Hereditary cancer-predisposing syndrome (4)
2	-	-	BARD1-related cancer predisposition (2)
1	-	-	BARD1-related disorder (1)
1	-	-	Breast and/or ovarian cancer (1)
1	-	-	Endometrial carcinoma (1)
1	-	-	Hereditary breast ovarian cancer syndrome (1)
1	-	-	Triple-Negative Breast Cancer Finding (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.88	D
PhyloP100		4.8
Vest4		0.89
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs587780021; hg19: chr2-215610566;