rs61754118

chr2-214728798-T-C

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.2212A>G(p.Ile738Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00768 in 1,614,204 control chromosomes in the GnomAD database, including 100 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0075 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0077 (91 hom.)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 2.38

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=0.0065450966).
• BP6: Variant 2-214728798-T-C is Benign according to our data. Variant chr2-214728798-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 136501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-214728798-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0075 (1143/152324) while in subpopulation AMR AF= 0.0131 (200/15290). AF 95% confidence interval is 0.0116. There are 9 homozygotes in gnomad4. There are 543 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1143 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BARD1	NM_000465.4	c.2212A>G	p.Ile738Val	missense_variant	11/11	ENST00000260947.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BARD1	ENST00000260947.9	c.2212A>G	p.Ile738Val	missense_variant	11/11	1	NM_000465.4	P2

Frequencies

GnomAD3 genomes AF: 0.00751 AC: 1143 AN: 152206 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00577

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0131

Gnomad ASJ AF: 0.0233

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.000470

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.00798

Gnomad OTH AF: 0.0191

GnomAD3 exomes AF: 0.00774 AC: 1945 AN: 251344 Hom.: 21 AF XY: 0.00774 AC XY: 1051 AN XY: 135836

Gnomad AFR exome AF: 0.00523

Gnomad AMR exome AF: 0.0116

Gnomad ASJ exome AF: 0.0276

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00317

Gnomad FIN exome AF: 0.000739

Gnomad NFE exome AF: 0.00839

Gnomad OTH exome AF: 0.0187

GnomAD4 exome AF: 0.00770 AC: 11262 AN: 1461880 Hom.: 91 Cov.: 32 AF XY: 0.00771 AC XY: 5610 AN XY: 727244

Gnomad4 AFR exome AF: 0.00702

Gnomad4 AMR exome AF: 0.0126

Gnomad4 ASJ exome AF: 0.0279

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00318

Gnomad4 FIN exome AF: 0.000899

Gnomad4 NFE exome AF: 0.00761

Gnomad4 OTH exome AF: 0.0112

GnomAD4 genome AF: 0.00750 AC: 1143 AN: 152324 Hom.: 9 Cov.: 32 AF XY: 0.00729 AC XY: 543 AN XY: 74498

Gnomad4 AFR AF: 0.00575

Gnomad4 AMR AF: 0.0131

Gnomad4 ASJ AF: 0.0233

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00310

Gnomad4 FIN AF: 0.000470

Gnomad4 NFE AF: 0.00798

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.00940 Hom.: 20

Bravo AF: 0.00884

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.00814 AC: 70

ExAC AF: 0.00732 AC: 889

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00971

EpiControl AF: 0.0123

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Benign:7

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
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	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	- -

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 24, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 18, 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. -
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	PreventionGenetics, part of Exact Sciences	Nov 28, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 18, 2020	- -

Hereditary cancer-predisposing syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Dec 18, 2015	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	May 11, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 19, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 17, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

BARD1: BP4, BS1, BS2 -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

BARD1, EXON11, c.2212A>G, p.Ile738Val, Heterozygous, Benign The BARD1 p.Ile738Val variant was identified in 5 of 1030 proband chromosomes (frequency: 0.005) from Polish, Australian and Belgian individuals or families with high risk BRCA1/2 negative breast and/or ovarian cancer and was identified in 5 of 1096 control chromosomes (frequency:0.005) from healthy individuals (Ratajska 2012, Gorringe 2008, De Brakeleer 2010). The variant was identified in a breast tumour, and assessed to be a neutral variant based on a transient apoptosis assay that showed no loss of function (Sauer 2005). In addition, the variant is located with the BRCT functional domain(s) increasing the liklihood that it may have clinical significance; however, protein modelling showed no effect on protein structure or stability (De Brakeleer 2010). The variant was also identified in dbSBP (ID: rs61754118) “With Likely benign allele”, ClinVar (classified benign by GeneDx, Ambry Genetics, Invitae, Vantari Genetics, Color Genomics, and Counsyl; and likely benign by Illumina), Clinivitae (4X) and the Zhejiang Colon Cancer Database (5x), but was not identified in Cosmic and MutDB databases. The variant was identified in control databases in 2066 (21 homozygous) of 277076 chromosomes at a frequency of 0.007 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017); being identified in the following populations at a frequency greater than 1%: Ashkenazi Jewish* in 285 of 10150 chromosomes (freq: 0.028), Other in 119 of 6464 chromosomes (freq: 0.018), and Latino in 389 of 34408 chromosomes (freq: 0.011). The p.Ile738Val residue is not conserved in mammals and four out of five 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	0.12
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	18
Dann	Benign	0.94
DEOGEN2	Benign	0.10	T;.;.;.;T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.81	T;T;T;T;T;.
MetaRNN	Benign	0.0065	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;.;.;.;.;.
MutationTaster	Benign	0.63	D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.43	N;.;.;.;.;.
REVEL	Benign	0.011
Sift	Benign	0.40	T;.;.;.;.;.
Sift4G	Benign	0.53	T;T;T;T;T;T
Polyphen		0.027	B;.;.;.;.;.
Vest4		0.081
MVP		0.66
MPC		0.074
ClinPred		0.0056	T
GERP RS		4.5
Varity_R		0.036
gMVP		0.51

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: rs61754118; hg19: chr2-215593522; COSMIC: COSV99638516; COSMIC: COSV99638516;