rs2228456

chr2-214730479-A-G

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.1933T>C(p.Cys645Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00376 in 1,613,948 control chromosomes in the GnomAD database, including 198 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict 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. C645Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.020 (104 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (94 hom.)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 1.56

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=0.00192523).
• BP6: Variant 2-214730479-A-G is Benign according to our data. Variant chr2-214730479-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 142135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0652 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BARD1	NM_000465.4	c.1933T>C	p.Cys645Arg	missense_variant	10/11	ENST00000260947.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BARD1	ENST00000260947.9	c.1933T>C	p.Cys645Arg	missense_variant	10/11	1	NM_000465.4	P2

Frequencies

GnomAD3 genomes AF: 0.0197 AC: 2994 AN: 152116 Hom.: 104 Cov.: 32

Gnomad AFR AF: 0.0673

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00929

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.00523 AC: 1314 AN: 251364 Hom.: 37 AF XY: 0.00372 AC XY: 506 AN XY: 135852

Gnomad AFR exome AF: 0.0702

Gnomad AMR exome AF: 0.00266

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.000739

Gnomad NFE exome AF: 0.000246

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00210 AC: 3063 AN: 1461714 Hom.: 94 Cov.: 30 AF XY: 0.00181 AC XY: 1313 AN XY: 727150

Gnomad4 AFR exome AF: 0.0683

Gnomad4 AMR exome AF: 0.00313

Gnomad4 ASJ exome AF: 0.00241

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.000543

Gnomad4 NFE exome AF: 0.000164

Gnomad4 OTH exome AF: 0.00525

GnomAD4 genome AF: 0.0197 AC: 2999 AN: 152234 Hom.: 104 Cov.: 32 AF XY: 0.0190 AC XY: 1416 AN XY: 74442

Gnomad4 AFR AF: 0.0673

Gnomad4 AMR AF: 0.00928

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000566

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.00389 Hom.: 38

Bravo AF: 0.0217

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0670 AC: 295

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00639 AC: 776

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Benign:7

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	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Counsyl	May 25, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 22, 2023	- -
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	Fulgent Genetics, Fulgent Genetics	May 24, 2022	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 22, 2016	- -
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	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 22, 2020	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 07, 2016	Variant summary:The c.1933T>C variant involves the alteration of a non-conserved nucleotide and causes change from medium size and polar (C) residue to large size and basic. 4/5 in silico tools predict a benign outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 1% (779/121331 chromosomes), predominantly observed in the African subpopulation at a frequency of 6.9% (720/10388 chromosomes) including 31 African homozygous occurrences. These frequencies exceed the maximal expected allele frequency for a pathogenic BARD1 variant of 0.0218%, suggesting this is a benign polymorphism found primarily in populations of African origin. One reputable clinical lab has classified this variant as benign (Ambry Genetics). It has previously been reported in patients with breast and ovarian cancer (Sauer 2005) without strong evidence for causality. Functional analyses showed this variant decreased the tumor suppression activity and apoptosis (Sauer 2005) and decreased the binding activity with poly(ADP-ribose) and BRCA1 (Li 2013). However, the in vivo implications of these functional findings have not been confirmed yet. Considering all, especially based on the high allele frequency in population cohorts, this variant is classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 25, 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. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 18, 2014	- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BARD1 p.Cys645Arg variant was identified in 1 of 504 proband chromosomes (frequency: 0.00198) from individuals or families with hereditary breast and ovarian cancer, and was also identified in 3 of 472 control chromosomes (frequency: 0.006) (De Brakeleer_2010_20077502, Sauer_2005_16061562). The variant was also identified in the following databases: dbSNP (ID: rs2228456) as “With Likely benign allele”, ClinVar (as likely benign by Illumina and benign by Ambry Genetics, Color Genomics, Counsyl, Invitae, and Quest Diagnostics), Clinvitae (3x), and Zhejiang Colon Cancer Database (3x). The variant was not identified in Cosmic, or MutDB databases. The variant was identified in control databases in 1841 of 277108 chromosomes (56 homozygous) at a frequency of 0.006644 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 1657 (55 homozygous) of 24032 chromosomes (freq: 0.06895), “Other” in 23 (1 homozygous) of 6464 chromosomes (freq: 0.003558), Latino in 99 of 34416 chromosomes (freq: 0.002877), European (Non-Finnish) in 29 of 126612 chromosomes (freq: 0.000229), Ashkenazi Jewish in 14 of 10148 chromosomes (freq: 0.00138), European (Finnish) in 17 of 25784 chromosomes (freq: 0.000659), and South Asian in 2 of 30782 chromosomes (freq: 0.000065), while the variant was not observed in the East Asian populations. Several functional studies identified the variant to be associated with breast and ovarian cancer, and may adversely affect the structure and function of the BRCT1 domain (Alshatwi_2012_23056176, Birrane_2007_17550235, Li_2013_23680151, Sauer_2005_16061562). The p.Cys645Arg residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. 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 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
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	14
Dann	Benign	0.70
DEOGEN2	Benign	0.077	T;.;.;.;T;.;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.73	T;T;T;T;T;.;.
MetaRNN	Benign	0.0019	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.35	N;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.2	N;.;.;.;.;.;N
REVEL	Benign	0.048
Sift	Benign	0.87	T;.;.;.;.;.;T
Sift4G	Benign	0.90	T;T;T;T;T;T;T
Polyphen		0.0010	B;.;.;.;.;.;.
Vest4		0.14
MVP		0.36
MPC		0.13
ClinPred		0.0027	T
GERP RS		4.6
Varity_R		0.25
gMVP		0.69

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: rs2228456; hg19: chr2-215595203; COSMIC: COSV104530919;