rs143914387

chr2-214809537-C-Achr2-214809537-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_000465.4(BARD1):c.33G>T(p.Gln11His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00157 in 1,577,884 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q11L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0016 (5 hom.)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:23
• Conservation: PhyloP100: 0.100

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 -11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 17 uncertain in NM_000465.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0070047975).
• BP6: Variant 2-214809537-C-A is Benign according to our data. Variant chr2-214809537-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127737.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=13, Uncertain_significance=1, Benign=5}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00165 (252/152328) while in subpopulation AMR AF= 0.00255 (39/15310). AF 95% confidence interval is 0.00192. There are 0 homozygotes in gnomad4. There are 149 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd at 251 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BARD1	NM_000465.4	c.33G>T	p.Gln11His	missense_variant	1/11	ENST00000260947.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BARD1	ENST00000260947.9	c.33G>T	p.Gln11His	missense_variant	1/11	1	NM_000465.4	P2

Frequencies

GnomAD3 genomes AF: 0.00165 AC: 251 AN: 152210 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00508

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00203

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00161 AC: 304 AN: 188348 Hom.: 1 AF XY: 0.00161 AC XY: 168 AN XY: 104332

Gnomad AFR exome AF: 0.000200

Gnomad AMR exome AF: 0.00244

Gnomad ASJ exome AF: 0.000671

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000412

Gnomad FIN exome AF: 0.00284

Gnomad NFE exome AF: 0.00199

Gnomad OTH exome AF: 0.00299

GnomAD4 exome AF: 0.00156 AC: 2229 AN: 1425556 Hom.: 5 Cov.: 74 AF XY: 0.00152 AC XY: 1074 AN XY: 706906

Gnomad4 AFR exome AF: 0.000245

Gnomad4 AMR exome AF: 0.00257

Gnomad4 ASJ exome AF: 0.000743

Gnomad4 EAS exome AF: 0.0000264

Gnomad4 SAS exome AF: 0.000420

Gnomad4 FIN exome AF: 0.00315

Gnomad4 NFE exome AF: 0.00166

Gnomad4 OTH exome AF: 0.00156

GnomAD4 genome AF: 0.00165 AC: 252 AN: 152328 Hom.: 0 Cov.: 34 AF XY: 0.00200 AC XY: 149 AN XY: 74488

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00508

Gnomad4 NFE AF: 0.00203

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.0149 Hom.: 330

Bravo AF: 0.00150

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00241 AC: 19

ExAC AF: 0.00162 AC: 189

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:23

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:10

Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27978560, 28135145, 25980754, 23056176, 26898890, 26787654, 27328445, 26979391, 27621404, 27498913, 26315354, 28528518, 28873162, 27443514) -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 22, 2022	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	BARD1: BS1 -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BARD1 p.Gln11His variant was identified in 4 of 3420 proband chromosomes (frequency: 0.001) from individuals or families with CRC and Lynch associated cancer (Pearlman 2017, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs143914387) as “with other allele”, and in the ClinVar and Clinvitae databases (as benign by Invitae and likely benign by GeneDx, Ambry Genetics, Illumina Clinical Services, Counsyl, and Quest Diagnostics Nichols Institute San Juan Capistrano). The variant was also identified in the Zhejiang Colon Cancer database 1x but no clinical information was provided. The variant was not identified in the Cosmic and MutDB databases. The variant was identified in the 1000 Genomes Project in 2 of 5000 chromosomes (frequency: 0.0004) and in the NHLBI GO Exome Sequencing Project in 19 of 7906 European American alleles (freq. 0.002). In addition, the variant was identified in control databases in 344 of 213748 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). Breakdown of the observations by population include African in 3 of 18190 chromosomes (freq: 0.0002), Other in 16 of 5410 chromosomes (freq: 0.003), Latino in 72 of 30394 chromosomes (freq: 0.002), European Non-Finnish in 178 of 92742 chromosomes (freq: 0.002), Ashkenazi Jewish in 7 of 8982 chromosomes (freq: 0.0008), European Finnish in 57 of 16012 chromosomes (freq: 0.004), and South Asian in 11 of 26824 chromosomes (freq: 0.0004) while the variant was not observed in the East Asian population. The p.Gln11His 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 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. -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 03, 2016	Variant summary: The c.33G>T (p.Gln11His) in BARD1 gene is a missense variant involves a non-conserved nucleotide and 5/5 in silico tools predict benign outcome. The variant is present in the control population dataset of ExAC at a frequency of 0.3% (115/37748 chrs tested), being most prevalent in Europeans (12/1030chrs tested), which exceeds the maximal expected allele frequency for a non-common pathogenic BARD1 variant (0.0002188). However, ExAC include a warning note that this variant is only covered in 18874 individuals (adjusted allele number = 37748). This means that the site is covered in fewer than 80% of the individuals in ExAC, which may indicate a low-quality site.The variant has been reported in affected individuals without strong evidence for causality. The variant of interest has been reported as Likely Benign/Benign by reputable databases/clinical laboratories. Taken all together, the variant was classified as Benign. -

Familial cancer of breast Benign:7

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. -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Oct 11, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 13, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 24, 2023	This variant is considered likely benign. 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	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 11, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 19, 2018	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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 11, 2021	- -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 04, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

May 01, 2023

- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Center of Medical Genetics and Primary Health Care

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	15
Dann	Uncertain	0.98
DEOGEN2	Benign	0.054	T;.;.;.;T;.;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.79	T;T;T;T;T;T;.
MetaRNN	Benign	0.0070	T;T;T;T;T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.4	L;.;L;.;.;L;.
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.97	N;.;.;.;.;.;N
REVEL	Benign	0.16
Sift	Benign	0.17	T;.;.;.;.;.;T
Sift4G	Benign	0.082	T;T;T;D;D;T;D
Polyphen		0.41	B;.;.;.;.;.;.
Vest4		0.24
MutPred		0.073		Loss of stability (P = 0.1698);Loss of stability (P = 0.1698);Loss of stability (P = 0.1698);Loss of stability (P = 0.1698);Loss of stability (P = 0.1698);Loss of stability (P = 0.1698);Loss of stability (P = 0.1698);
MVP		0.93
MPC		0.12
ClinPred		0.013	T
GERP RS		-0.27
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.13
gMVP		0.49

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: rs143914387; hg19: chr2-215674261;