rs200359745

chr2-214781158-A-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000465.4(BARD1):c.716T>A(p.Leu239Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000577 in 1,577,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L239L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000058 (0 hom.)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:15 B:2
• Conservation: PhyloP100: -0.116

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06748453).
• BP6: Variant 2-214781158-A-T is Benign according to our data. Variant chr2-214781158-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127746.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=15, Likely_benign=2}.
• BS2: High AC in GnomAd at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BARD1	NM_000465.4	c.716T>A	p.Leu239Gln	missense_variant	4/11	ENST00000260947.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BARD1	ENST00000260947.9	c.716T>A	p.Leu239Gln	missense_variant	4/11	1	NM_000465.4	P2

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000101 AC: 22 AN: 217412 Hom.: 0 AF XY: 0.000102 AC XY: 12 AN XY: 117248

Gnomad AFR exome AF: 0.0000645

Gnomad AMR exome AF: 0.0000375

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000434

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000174

Gnomad OTH exome AF: 0.000198

GnomAD4 exome AF: 0.0000575 AC: 82 AN: 1425466 Hom.: 0 Cov.: 34 AF XY: 0.0000679 AC XY: 48 AN XY: 706924

Gnomad4 AFR exome AF: 0.0000636

Gnomad4 AMR exome AF: 0.0000552

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000573

Gnomad4 OTH exome AF: 0.000102

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74486

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000641 Hom.: 0

Bravo AF: 0.0000416

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000107 AC: 13

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:15 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial cancer of breast Uncertain:5 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 239 of the BARD1 protein (p.Leu239Gln). This variant is present in population databases (rs200359745, gnomAD 0.02%). This missense change has been observed in individual(s) with personal or family history of breast and/or ovarian cancer (PMID: 26976419, 31159747, 35595798). ClinVar contains an entry for this variant (Variation ID: 127746). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect BARD1 function (PMID: 30925164). Studies have shown that this missense change is associated with altered splicing resulting in multiple RNA products (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
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]. -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Aug 23, 2022	The BARD1 c.716T>A (p.Leu239Gln) missense change has a maximum subpopulation frequency of 0.016% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant has been reported in the literature in individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 26976419, 31159747, 32039725, 33471991). It has also been reported in one individual in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). Algorithms that predict the impact of sequence changes on splicing indicate that this change may affect splicing. RNA studies indicate that this variant strengthens a cryptic splice within exon 4 of the BARD1 gene and causes leaky splicing (PMID: 31275557). The in silico tool REVEL predicts a benign effect on protein function and functional analysis indicates that this variant has homology-directed repair (HDR) comparable to the wild-type (PMID: 30925164). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 16, 2017	- -

Hereditary cancer-predisposing syndrome Uncertain:4 Benign:1

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jun 17, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 19, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 28, 2022	The p.L239Q variant (also known as c.716T>A), located in coding exon 4 of the BARD1 gene, results from a T to A substitution at nucleotide position 716. The leucine at codon 239 is replaced by glutamine, an amino acid with dissimilar properties. This alteration has been reported in individuals with a personal or family history of breast and/or ovarian cancer (da Costa E Silva Carvalho S et al. BMC Med Genomics, 2020 02;13:21; Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535; Tung N et al. J. Clin. Oncol., 2016 May;34:1460-8; Young EL et al. J. Med. Genet., 2016 06;53:366-76). This alteration was found to be functional in a homology-directed DNA repair (HDR) assay (Adamovich AI et al. PLoS Genet., 2019 03;15:e1008049). RNA analyses have shown that this alteration leads to aberrant splicing by creating a new alternate donor site (Shirley BC et al. F1000Res, 2018 Dec;7:1908).This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	May 23, 2018	- -

not specified Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 10, 2019	Variant summary: BARD1 c.716T>A (p.Leu239Gln) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 217412 control chromosomes, predominantly at a frequency of 0.00017 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is somewhat lower than the expected maximum for a pathogenic variant in BARD1 causing Hereditary Breast and Ovarian Cancer (0.00017 vs 0.00025), allowing no clear conclusions about variant significance. c.716T>A has been reported in the literature in individuals with a personal or family history of breast and/or ovarian cancer (e.g. Tung_2016, Tsaousis_2019, Adamovich_2019) and other tumor phenotypes (Adamovich_2019); however without strong evidence for causality. These reports therefore do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. One publication reported experimental evidence demonstrating that the variant protein is fully functional in homology-directed DNA repair (HDR) (Adamovich_2019). Ten other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation: nine laboratories cited the variant as uncertain significance, while one cited the variant as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 25, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 15, 2023	In the published literature, this variant has been reported in individuals with breast cancer (PMID: 26976419 (2016), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BARD1), 35264596 (2022)), as well as unaffected individuals (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BARD1)). A functional study reported that this variant has proficient homology-directed repair (HDR) activity (PMID: 30925164 (2019)). The frequency of this variant in the general population, 0.00016 (19/118622 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on BARD1 mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2023	In silico analysis supports a deleterious effect on splicing; In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies are inconclusive: homology-directed repair activity comparable to wild type, but may cause abnormal splicing (Shirley et al., 2018; Adamovich et al., 2019); Observed in individuals with personal or family history of breast or other cancers and also in unaffected controls (Tung et al., 2016; Tsaousis et al., 2019; da Costa e Silva Carvalho et al., 2020; Dorling et al., 2021; Guindalini et al., 2022); This variant is associated with the following publications: (PMID: 32039725, 26976419, 26787654, 27720647, 30925164, 31159747, 31275557, 35595798, 33471991, 35264596) -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 13, 2022

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	15
Dann	Benign	0.26
DEOGEN2	Benign	0.080	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.55	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.067	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.020	N;.
REVEL	Benign	0.071
Sift	Benign	0.61	T;.
Sift4G	Benign	0.51	T;T
Polyphen		0.014	B;.
Vest4		0.14
MVP		0.56
MPC		0.079
ClinPred		0.018	T
GERP RS		-4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.066
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.57		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.57		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs200359745; hg19: chr2-215645882;