rs5031011

Positions:

• chr2-214767468-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000465.4(BARD1):​c.1568+14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.345 in 1,606,412 control chromosomes in the GnomAD database, including 96,897 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9520 hom., cov: 32)
  • Exomes 𝑓: 0.34 (87377 hom.)
• Consequence: BARD1 NM_000465.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.295

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-214767468-G-A is Benign according to our data. Variant chr2-214767468-G-A is described in ClinVar as [Benign]. Clinvar id is 256214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.389 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BARD1	NM_000465.4	c.1568+14C>T		intron_variant		ENST00000260947.9	NP_000456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9	c.1568+14C>T		intron_variant		1	NM_000465.4	ENSP00000260947	P2

Frequencies

GnomAD3 genomes AF: 0.351 AC: 53226 AN: 151760 Hom.: 9506 Cov.: 32

Gnomad AFR AF: 0.346

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.305

Gnomad ASJ AF: 0.395

Gnomad EAS AF: 0.373

Gnomad SAS AF: 0.404

Gnomad FIN AF: 0.452

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.342

Gnomad OTH AF: 0.362

GnomAD3 exomes AF: 0.357 AC: 89442 AN: 250632 Hom.: 16340 AF XY: 0.359 AC XY: 48642 AN XY: 135468

Gnomad AFR exome AF: 0.347

Gnomad AMR exome AF: 0.287

Gnomad ASJ exome AF: 0.392

Gnomad EAS exome AF: 0.366

Gnomad SAS exome AF: 0.394

Gnomad FIN exome AF: 0.452

Gnomad NFE exome AF: 0.348

Gnomad OTH exome AF: 0.340

GnomAD4 exome AF: 0.344 AC: 500769 AN: 1454534 Hom.: 87377 Cov.: 32 AF XY: 0.346 AC XY: 250816 AN XY: 724016

Gnomad4 AFR exome AF: 0.341

Gnomad4 AMR exome AF: 0.290

Gnomad4 ASJ exome AF: 0.383

Gnomad4 EAS exome AF: 0.358

Gnomad4 SAS exome AF: 0.397

Gnomad4 FIN exome AF: 0.455

Gnomad4 NFE exome AF: 0.336

Gnomad4 OTH exome AF: 0.346

GnomAD4 genome AF: 0.351 AC: 53277 AN: 151878 Hom.: 9520 Cov.: 32 AF XY: 0.356 AC XY: 26462 AN XY: 74232

Gnomad4 AFR AF: 0.346

Gnomad4 AMR AF: 0.304

Gnomad4 ASJ AF: 0.395

Gnomad4 EAS AF: 0.373

Gnomad4 SAS AF: 0.404

Gnomad4 FIN AF: 0.452

Gnomad4 NFE AF: 0.342

Gnomad4 OTH AF: 0.362

Alfa AF: 0.342 Hom.: 18469

Bravo AF: 0.334

Asia WGS AF: 0.374 AC: 1299 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 31, 2015

- -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.7
DANN	Benign	0.79

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

Publications

LitVar

Other links and lift over

dbSNP: rs5031011; hg19: chr2-215632192; COSMIC: COSV53615058;