rs587781979

chr2-214809529-ATCCTCGGCTGCCGGT-Achr2-214809529-ATCCTCGGCTGCCGGT-ATCCTCGGCTGCCGGTTCCTCGGCTGCCGGT

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4BS2

The NM_000465.4(BARD1):c.26_40del(p.Asn9_Arg13del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000448 in 1,585,944 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. N9N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

BARD1
NM_000465.4 inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:11

Conservation

PhyloP100: 3.81

Variant links:

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]

BARD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_000465.4.

BS2

High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BARD1	NM_000465.4 linkuse as main transcript	c.26_40del	p.Asn9_Arg13del	inframe_deletion	1/11	ENST00000260947.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BARD1	ENST00000260947.9 linkuse as main transcript	c.26_40del	p.Asn9_Arg13del	inframe_deletion	1/11	1	NM_000465.4	P2	Q99728-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000400

AC:

AN:

200152

Hom.:

AF XY:

0.0000360

AC XY:

AN XY:

111056

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000460

Gnomad OTH exome

AF:

0.000191

GnomAD4 exome

AF:

0.0000439

AC:

AN:

1433646

Hom.:

AF XY:

0.0000464

AC XY:

AN XY:

711440

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000261

Gnomad4 SAS exome

AF:

0.000143

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000445

Gnomad4 OTH exome

AF:

0.0000169

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152298

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 08, 2021	DNA sequence analysis of the BARD1 gene demonstrated a 15 base pair deletion in exon 1, c.26_40del. This in-frame deletion is predicted to result in the deletion of five amino acid residues, p.Asn9_Arg13del. This deletion has been previously described in an individual with a personal or family history of breast and/or ovarian cancer (PMID: 311597470). This sequence change has been described in the gnomAD database with a frequency of 0.011% in the South Asian subpopulation (dbSNP rs587781979). The functional significance of this sequence change is not known at present and its contribution to this individual's disease phenotype cannot definitively be determined. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 18, 2020	Variant summary: BARD1 c.26_40del15 (p.Asn9_Arg13del) results in an in-frame deletion that is predicted to remove 5 amino acids from the encoded protein. The variant allele was found at a frequency of 4e-05 in 200152 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.26_40del15 has been reported in the literature in individuals affected colorectal cancer and/or polyps or with personal or family history of breast and/or ovarian cancer (Yurgelun_2015, Tsaousis_2019). These reports however, do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary cancer-predisposing syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 12, 2022	The c.26_40del15 variant (also known as p.N9_R13del) is located in coding exon 1 of the BARD1 gene. This variant results from an in-frame deletion of 15 nucleotides at positions 26 to 40 and causes the deletion of five amino acid residues at codons 9 through 13. This alteration has been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition. (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This deleted region is not well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 13, 2023	This variant causes an in-frame deletion of five amino acids from the BARD1 protein, in a region that is not known to encode important functional domains. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). This variant has also been identified in 10/231508 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 14, 2022	In-frame deletion of 5 amino acids in a non-repeat region; In silico analysis supports that this variant does not alter protein structure/function; Observed in an individual with a Lynch syndrome-associated cancer and/or colon polyps, as well as individuals undergoing a multigene panel test for hereditary cancer risk (Yurgelun 2015, Mu 2016, Tsaousis 2019); This variant is associated with the following publications: (PMID: 27720647, 25980754, 31159747, 27535533) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 28, 2023	In the published literature, this variant has been reported in affected individuals with hereditary breast and/or ovarian cancer (PMID: 31159747 (2019)), colorectal cancer and/or Lynch Syndrome (PMID:25980754 (2015)), biliary tract cancer (PMID: 36243179 (2022)), and pediatric cancer (PMID:26580448 (2015)). The frequency of this variant in the general population, 0.00011 (3/27484 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. -

Familial cancer of breast

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Dec 23, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 07, 2024	This variant, c.26_40del, results in the deletion of 5 amino acid(s) of the BARD1 protein (p.Asn9_Arg13del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs587781979, gnomAD 0.01%). This variant has been observed in individual(s) with clinical features of Lynch syndrome, and in an individual with acute lymphoblastic leukemia and personal or family history of breast and/or ovarian cancer, in an individual with clinical features of Lynch syndrome, and in an individual with acute lymphoblastic leukemia (PMID: 25980754, 26580448, 31159747). This variant is also known as R5_N9del. ClinVar contains an entry for this variant (Variation ID: 141745). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

BARD1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 14, 2024

The BARD1 c.26_40del15 variant is predicted to result in an in-frame deletion (p.Asn9_Arg13del). This variant has been reported in individuals undergoing hereditary cancer testing (example: Yurgelun et al. 2015. PubMed ID: 25980754, Subject ID 1086153107; Tsaousis et al. 2019. PubMed ID: 31159747, Table S5). This variant has been reported in the gnomAD public population database in 10 of ~232,000 alleles and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/141745/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over