rs587781282

chr2-214780778-GTGGTGAAGAACATTCAGGCAA-Gchr2-214780778-G-GTGGTGAAGAACATTCAGGCAA

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4 BP6_Very_Strong BA1

The NM_000465.4(BARD1):c.1075_1095del(p.Leu359_Pro365del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.023 in 1,614,032 control chromosomes in the GnomAD database, including 759 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L359L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.028 (85 hom., cov: 32)
  • Exomes 𝑓: 0.022 (674 hom.)
• Consequence: BARD1 NM_000465.4 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 2.10

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 -14 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000465.4.
• BP6: Variant 2-214780778-GTGGTGAAGAACATTCAGGCAA-G is Benign according to our data. Variant chr2-214780778-GTGGTGAAGAACATTCAGGCAA-G is described in ClinVar as [Likely_benign]. Clinvar id is 140795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-214780778-GTGGTGAAGAACATTCAGGCAA-G is described in Lovd as [Likely_benign]. Variant chr2-214780778-GTGGTGAAGAACATTCAGGCAA-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0711 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BARD1	NM_000465.4	c.1075_1095del	p.Leu359_Pro365del	inframe_deletion	4/11	ENST00000260947.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BARD1	ENST00000260947.9	c.1075_1095del	p.Leu359_Pro365del	inframe_deletion	4/11	1	NM_000465.4	P2

Frequencies

GnomAD3 genomes AF: 0.0282 AC: 4294 AN: 152090 Hom.: 85 Cov.: 32

Gnomad AFR AF: 0.0404

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.0379

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.0478

Gnomad SAS AF: 0.0774

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0183

Gnomad OTH AF: 0.0316

GnomAD3 exomes AF: 0.0289 AC: 7261 AN: 251308 Hom.: 169 AF XY: 0.0304 AC XY: 4124 AN XY: 135812

Gnomad AFR exome AF: 0.0432

Gnomad AMR exome AF: 0.0337

Gnomad ASJ exome AF: 0.0120

Gnomad EAS exome AF: 0.0439

Gnomad SAS exome AF: 0.0705

Gnomad FIN exome AF: 0.00356

Gnomad NFE exome AF: 0.0179

Gnomad OTH exome AF: 0.0324

GnomAD4 exome AF: 0.0224 AC: 32769 AN: 1461824 Hom.: 674 AF XY: 0.0238 AC XY: 17297 AN XY: 727208

Gnomad4 AFR exome AF: 0.0432

Gnomad4 AMR exome AF: 0.0340

Gnomad4 ASJ exome AF: 0.0120

Gnomad4 EAS exome AF: 0.0583

Gnomad4 SAS exome AF: 0.0714

Gnomad4 FIN exome AF: 0.00311

Gnomad4 NFE exome AF: 0.0171

Gnomad4 OTH exome AF: 0.0272

GnomAD4 genome AF: 0.0282 AC: 4294 AN: 152208 Hom.: 85 Cov.: 32 AF XY: 0.0284 AC XY: 2112 AN XY: 74426

Gnomad4 AFR AF: 0.0405

Gnomad4 AMR AF: 0.0379

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.0477

Gnomad4 SAS AF: 0.0776

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.0183

Gnomad4 OTH AF: 0.0308

Alfa AF: 0.00648 Hom.: 13

Bravo AF: 0.0308

Asia WGS AF: 0.0570 AC: 196 AN: 3478

EpiCase AF: 0.0230

EpiControl AF: 0.0226

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Benign:7

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Jul 06, 2016	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 24, 2023	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 27, 2023	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 08, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jul 19, 2016	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BARD1 p.Leu359_Pro365del variant was identified in 19 of 926 proband chromosomes (frequency: 0.0205) from individuals or families with hereditary breast and ovarian cancer and was present in 4 of 140 control chromosomes (frequency: 0.03) from healthy individuals, and is reported in the literature as a polymorphism (De Brakeleer 2010, De Brakeleer 2015, Ishitobi 2003, Liu 2017, Irminger-Finger 2015). The variant was also identified in ClinVar as benign (by Ambry Genetics, GeneDx, Invitae, and Counsyl), and the Zhejiang Colon Cancer Database. The variant was not identified in Cosmic, and MutDB databases. The variant was identified in control databases in 7807 of 277012 chromosomes at a frequency of 0.03 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: South Asian (52 homozygous) in 2152 of 30774 chromosomes (freq: 0.07), East Asian (8 homozygous) in 834 of 18854 chromosomes (freq: 0.044), African (9 homozygous) in 986 of 24026 chromosomes (freq: 0.041), Latino (2 homozygous) in 1167 of 34380 chromosomes (freq: 0.034), Other in 209 of 6462 chromosomes (freq: 0.032), European (Non-Finnish) in 2254 of 126574 chromosomes (freq: 0.018), Ashkenazi Jewish in 118 of 10152 chromosomes (freq: 0.012). This variant is an in-frame deletion resulting in the removal of a 7 amino acid residues from codon 359 to 365; the impact of this alteration on BARD1 protein function is not known. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Hereditary cancer-predisposing syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 14, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 17, 2012	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 20, 2020	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2018	- -

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs28997575; hg19: chr2-215645502;