rs147215925

Variant names:

• chr2-214730435-T-C
• rs147215925
• NM_000465.4:c.1977A>G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000465.4(BARD1):​c.1977A>G​(p.Arg659Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00314 in 1,613,972 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0022 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (11 hom.)
• Consequence: BARD1 NM_000465.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:22
• Conservation: PhyloP100: 0.699

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 2-214730435-T-C is Benign according to our data. Variant chr2-214730435-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127727.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=7, Likely_benign=10}. Variant chr2-214730435-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.699 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00223 (340/152282) while in subpopulation NFE AF= 0.00419 (285/68020). AF 95% confidence interval is 0.00379. There are 3 homozygotes in gnomad4. There are 149 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 340 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BARD1	NM_000465.4	c.1977A>G	p.Arg659Arg	synonymous_variant	Exon 10 of 11	ENST00000260947.9	NP_000456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9	c.1977A>G	p.Arg659Arg	synonymous_variant	Exon 10 of 11	1	NM_000465.4	ENSP00000260947.4

Frequencies

GnomAD3 genomes AF: 0.00223 AC: 340 AN: 152164 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00635

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00419

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00197 AC: 494 AN: 251398 Hom.: 1 AF XY: 0.00175 AC XY: 238 AN XY: 135872

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000867

Gnomad ASJ exome AF: 0.00784

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.00291

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00323 AC: 4728 AN: 1461690 Hom.: 11 Cov.: 30 AF XY: 0.00310 AC XY: 2256 AN XY: 727142

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.000805

Gnomad4 ASJ exome AF: 0.00651

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00124

Gnomad4 NFE exome AF: 0.00382

Gnomad4 OTH exome AF: 0.00305

GnomAD4 genome AF: 0.00223 AC: 340 AN: 152282 Hom.: 3 Cov.: 32 AF XY: 0.00200 AC XY: 149 AN XY: 74466

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00635

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00419

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00392 Hom.: 6

Bravo AF: 0.00194

Asia WGS AF: 0.000289 AC: 2 AN: 3476

EpiCase AF: 0.00431

EpiControl AF: 0.00296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:22

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:6

Jun 06, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26075229, 32025336, 25994375, 26738429, 26329992, 28030839, 22433386, 21344236, 28821472, 26787654, 30441849, 31142030, 30374176) -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BARD1: BP4, BS1, BS2 -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 13, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial cancer of breast Uncertain:1 Benign:6

Feb 24, 2023

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Sep 24, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 02, 2018

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2018

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

The BARD1 variant designated as NM_000465.3:c.1977A>G (p.Arg659=) is classified as likely benign. The variant is present in approximately 1 in every 170 individuals with European ancestry (exac.broadinstitute.org), which is more common than cancer risk variants. In one observed family, the allele did not travel with breast cancer in the family, providing additional evidence that the BARD1 p.Arg659= is benign. This variant has been classified as likely benign by other laboratories (ClinVar Variation ID: 127727). Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives a <1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter BARD1 function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This reclassification analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. -

Nov 09, 2017

Counsyl

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:4

Nov 30, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 15, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jul 12, 2017

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 09, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not specified Benign:3

Nov 16, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BARD1 c.1977A>G alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing; however ESEfinder predicts binding motif alterations for RNA splicing enhancers. Supporting the prediction of altered binding motifs, a functional study showed that this variant was associated with a transcript lacking exons 2-9 resulting in a very short open reading frame (p.Cys53_Trp635delinsfsX12) in addition to full-length transcript at a ratio of 3.8 (full-length to short; Ratajska_2012), which was not seen in controls. In a recent functional study examining the effect of variant at the cellular level, the authors observed a significant increase of telomere abnormalities (Pilyugin_2017). Pathogenic variants in BARD1 gene confer increased risk of breast and/or ovarian cancer. Monoallelic germline mutations in BARD1 are estimated to confer up to a 3 fold increased risk for breast cancer compared to the general population (PMID: 22264603). Given the unknown clinical effect of this occasional splicing abnormality, the importance of these in vitro studies is unclear. This variant was found in 572/ 279550 control chromosomes (including one homozygous occurrence) at a frequency of 0.002, which is more than 8 times greater than the maximal expected frequency of a pathogenic allele (0.00025) in this gene. Additionally, the observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database and publications is approximately 30.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in BARD1 causing Hereditary Breast and Ovarian Cancer phenotype (0.00025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. c.1977A>G has been reported in the literature and in one poster from Ambry Genetics in individuals affected with Hereditary Breast and Ovarian Cancer (Ratajska_2012, Ratajska_2015, Pesaran_2013) with a combined OR of 2.76. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Jul 21, 2020

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast and/or ovarian cancer Benign:1

Jun 01, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BARD1-related disorder Benign:1

May 16, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Malignant tumor of breast Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BARD1 p.Arg659= variant was identified in 50 of 25,074 proband chromosomes (frequency: 0.002) from individuals or families with basal cell carcinoma and hereditary breast and ovarian cancer and was present in 14 of 9414 control chromosomes (frequency: 0.001) from healthy individuals (Suszynska 2019, Cho 2018). The variant was identified in dbSNP (rs147215925) as “with other allele” and ClinVar (classified as likely benign by GeneDx, Ambry Genetics, Mendelics and 4 other submitters, benign by Invitae, Color and Quest Diagnostics and uncertain significance by Integrated Genetics and Prevention Genetics). The variant was identified in control databases in 576 of 282,800 chromosomes (1 homozygous) at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 81 of 10,366 chromosomes (freq: 0.008), Other in 24 of 7216 chromosomes (freq: 0.003), European in 398 of 129,128 chromosomes (freq: 0.003), Finnish in 33 of 25,118 chromosomes (freq: 0.001), Latino in 30 of 35,438 chromosomes (freq: 0.0008), African in 9 of 24,968 chromosomes (freq: 0.0004), South Asian in 1 of 30,612 chromosomes (freq: 0.00003), while the variant was not observed in the East Asian population. The p.Arg659= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs at a non-highly conserved nucleotide outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	9.4
DANN	Benign	0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs147215925; hg19: chr2-215595159; COSMIC: COSV99638173;