rs3738888

chr2-214730440-G-Achr2-214730440-G-Cchr2-214730440-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000465.4(BARD1):c.1972C>T(p.Arg658Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00855 in 1,613,728 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts 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. R658H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0073 (15 hom., cov: 32)
  • Exomes 𝑓: 0.0087 (54 hom.)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:19
• Conservation: PhyloP100: 5.27

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 (MetaRNN=0.0056836605).
• BP6: Variant 2-214730440-G-A is Benign according to our data. Variant chr2-214730440-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 136500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-214730440-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00731 (1113/152168) while in subpopulation EAS AF= 0.00986 (51/5170). AF 95% confidence interval is 0.00787. There are 15 homozygotes in gnomad4. There are 582 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1114 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BARD1	NM_000465.4	c.1972C>T	p.Arg658Cys	missense_variant	10/11	ENST00000260947.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BARD1	ENST00000260947.9	c.1972C>T	p.Arg658Cys	missense_variant	10/11	1	NM_000465.4	P2

Frequencies

GnomAD3 genomes AF: 0.00733 AC: 1114 AN: 152050 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00220

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.00661

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00984

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.0151

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00846

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00843 AC: 2118 AN: 251368 Hom.: 10 AF XY: 0.00785 AC XY: 1067 AN XY: 135856

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.0125

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0115

Gnomad SAS exome AF: 0.00408

Gnomad FIN exome AF: 0.0128

Gnomad NFE exome AF: 0.00866

Gnomad OTH exome AF: 0.00865

GnomAD4 exome AF: 0.00868 AC: 12682 AN: 1461560 Hom.: 54 Cov.: 30 AF XY: 0.00836 AC XY: 6077 AN XY: 727102

Gnomad4 AFR exome AF: 0.00137

Gnomad4 AMR exome AF: 0.0112

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.0103

Gnomad4 SAS exome AF: 0.00452

Gnomad4 FIN exome AF: 0.0126

Gnomad4 NFE exome AF: 0.00922

Gnomad4 OTH exome AF: 0.00664

GnomAD4 genome AF: 0.00731 AC: 1113 AN: 152168 Hom.: 15 Cov.: 32 AF XY: 0.00782 AC XY: 582 AN XY: 74388

Gnomad4 AFR AF: 0.00219

Gnomad4 AMR AF: 0.00667

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00986

Gnomad4 SAS AF: 0.00374

Gnomad4 FIN AF: 0.0151

Gnomad4 NFE AF: 0.00844

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00713 Hom.: 10

Bravo AF: 0.00749

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.0150 AC: 58

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00779 AC: 67

ExAC AF: 0.00793 AC: 963

Asia WGS AF: 0.00722 AC: 26 AN: 3478

EpiCase AF: 0.00725

EpiControl AF: 0.00705

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Jun 03, 2016	- -
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	Nov 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not specified Benign:5

Likely 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	Genetic Services Laboratory, University of Chicago	May 27, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 14, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 02, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 22, 2016	- -

Hereditary cancer-predisposing syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 02, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 26, 2014	This alteration is classified as 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. -
Likely benign, no assertion criteria provided	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Sep 27, 2021	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	May 30, 2021	- -

Triple-Negative Breast Cancer Finding Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Lab. Molecular Oncology, VUB, Free University of Brussels

Feb 01, 2015

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2024

BARD1: BP4, BS1, BS2 -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BARD1 p.Arg658Cys variant was identified in 9 of 2368 proband chromosomes (frequency: 0.004) from individuals or families with breast and/or ovarian cancer (Karppinen 2004, Klonowska 2015, Vahteristo 2006). The variant was also identified in the following databases: dbSNP (ID: rs3738888) as “With other allele”, ClinVar (6x, as benign by GeneDx, Ambry Genetics, Invitae, Color Genomics.Inc, and as likely benign by Illumina Clinical Services, Counsyl), Clinvitae (4x, as benign and likely benign), and Zhejiang Colon Cancer Database (6x, as probably pathogenic). The variant was not identified in Cosmic nor MutDB databases. The variant was identified in control databases in 2270 (11 homozygous) of 277098 chromosomes at a frequency of 0.008 in the following populations: Finnish in 336 of 25784 chromosomes (freq. 0.013), Latino in 425 of 34414 chromosomes (freq. 0.012), East Asian in 206 of 18868 chromosomes (freq. 0.01), European in 1067 of 126610 chromosomes (freq. 0.0084), other in 53 of 6462 chromosomes (freq. 0.008), South Asian in 125 of 30782 chromosomes (freq. 0.004), and African in 58 of 2403 chromosomes (freq. 0.0024), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). Although the p.Arg658Cys residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. 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. There are conflicting predictions in the literature regarding the clinical significance of the p.Arg658Cys variant. Some studies refer to this variant as potentially pathological (Klonowska 2015), but functional studies do not predict clinical significance for this variant although it is in a functional domain (Lee 2015). In another study this variant has been utilized as putative benign polymorphism in multiple functional assays (Sauer 2005). A co-occurring pathogenic BRCA1 variant (c.709G>T, p.Glu237X) was identified in 1 individual with breast cancer by our laboratory, increasing the likelihood that p.Arg658Cys variant does not have clinical significance. 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. -

Hereditary cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Hereditary breast ovarian cancer syndrome Benign:1

Likely 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
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.39	T;.;.;.;T;.;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;.;.
MetaRNN	Benign	0.0057	T;T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.1	M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-4.0	D;.;.;.;.;.;D
REVEL	Benign	0.10
Sift	Uncertain	0.0080	D;.;.;.;.;.;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D
Polyphen		0.99	D;.;.;.;.;.;.
Vest4		0.32
MVP		0.89
MPC		0.20
ClinPred		0.049	T
GERP RS		5.8
Varity_R		0.40
gMVP		0.51

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: rs3738888; hg19: chr2-215595164; COSMIC: COSV53616840;