chr2-214730457-T-TCATACTTTTCTTCCTGTTCA

Position:

• chr2-214730457-T-TCATACTTTTCTTCCTGTTCA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_000465.4(BARD1):​c.1954_1955insTGAACAGGAAGAAAAGTATG​(p.Glu652ValfsTer69) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000905 in 1,614,002 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000094 (0 hom.)
• Consequence: BARD1 NM_000465.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 6.51

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.163 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PP5: Variant 2-214730457-T-TCATACTTTTCTTCCTGTTCA is Pathogenic according to our data. Variant chr2-214730457-T-TCATACTTTTCTTCCTGTTCA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 127725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BARD1	NM_000465.4	c.1954_1955insTGAACAGGAAGAAAAGTATG	p.Glu652ValfsTer69	frameshift_variant	10/11	ENST00000260947.9	NP_000456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9	c.1954_1955insTGAACAGGAAGAAAAGTATG	p.Glu652ValfsTer69	frameshift_variant	10/11	1	NM_000465.4	ENSP00000260947	P2

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000637 AC: 16 AN: 251374 Hom.: 0 AF XY: 0.0000883 AC XY: 12 AN XY: 135858

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: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000937 AC: 137 AN: 1461736 Hom.: 0 Cov.: 30 AF XY: 0.0000949 AC XY: 69 AN XY: 727158

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000119

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74458

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000843 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial cancer of breast Pathogenic:6

Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Apr 13, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 21, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 07, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 24, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This sequence change creates a premature translational stop signal (p.Glu652Valfs*69) in the BARD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 126 amino acid(s) of the BARD1 protein. This variant is present in population databases (rs587780024, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 20077502, 25452441, 26681312). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 127725). RT-PCR analysis has shown that this variant did not activate nonsense mediated decay, as equal amounts of the mutant and wild-type alleles were expressed in the leukocytes of affected individuals (PMID: 20077502). This truncating variant does lead to the loss of the last 126 amino acids of the BARD1 protein (Glu652-Ser777), removing completely the most C-terminal of the two BRCT repeats (residues 669-777) (PMID: 26315354, 17550235). While the functional significance of deleting the second BRCT domain has not been addressed experimentally, studies suggest that both BRCT repeats in BARD1 are necessary for its normal functioning (PMID: 17550235, 26738429, 17848578). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -

not provided Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2024	Frameshift variant predicted to result in abnormal protein length as the last 126 amino acids are replaced with 68 different amino acids, and other similar variants have been reported in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with personal or family history of breast and/or ovarian cancer (PMID: 20077502, 25452441, 28888541, 29790872, 31173646, 31036035, 35626031); This variant is associated with the following publications: (PMID: 31341520, 26681312, 28008555, 26738429, 28152038, 20077502, 25452441, 26556299, 26315354, 17848578, 26546047, 29922827, 29790872, 31036035, 31173646, 33099839, 32679805, 33598691, 35626031, 32923906, 36187937, 28888541, 34326862, 35969835, 17550235, 37688579) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 20, 2021	This frameshift variant alters the translational reading frame of the BARD1 mRNA and causes the premature termination of BARD1 protein synthesis. The frequency of this variant in the general population, 0.00012 (15/129114 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals/families with breast cancer (PMIDs: 31036035 (2019), 26681312 (2015), 25452441 (2015), 20077502 (2010)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 15, 2015	The c.1935_1954dup20 pathogenic mutation, located in coding exon 10 of the BARD1 gene, results from a duplication of 20 nucleotides from positions 1935 to 1954, causing a translational frameshift with a predicted alternate stop codon. This mutation has previously been reported in a high risk breast/ovarian cancer family from Belgium (De Brakeleer S et al. Hum. Mutat. 2010 Mar;31(3):E1175-85) and in 3 of 1824 triple negative breast cancer patients unselected for family history (Couch FJ et al. J. Clin. Oncol. 2015 Feb;33(4):304-11, Supplementary Data). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 06, 2022	This variant inserts 20 nucleotides in exon 10 of the BARD1 gene, creating a frameshift and premature translation stop signal. This variant is expected to disrupt the last 126 amino acids of the BARD1 protein, including the functionally important BRCT2 domain (a.a. 667-777) (PMID: 17848578) and is likely to result in a non-functional protein product. This variant has been reported in individuals affected with breast cancer (PMID: 20077502, 25452441, 26681312, 31036035). This variant has also been reported in at least one individual with neuroblastoma (PMID: 33598691). This variant has been identified in 17/282768 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BARD1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 10, 2020

Variant summary: BARD1 c.1935_1954dup20 (p.Glu652ValfsX69) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One report in the literature indicates that the variant does not activate nonsense mediated decay, as RT-PCR analysis showed equal amounts of the mutant and wild-type alleles expressed in leukocytes from individuals with the variant (DeBrakeleer_2010). The variant allele was found at a frequency of 6.4e-05 in 251374 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BARD1 causing Hereditary Breast and Ovarian Cancer (6.4e-05 vs 0.00025), allowing no conclusion about variant significance. c.1935_1954dup20 has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (e.g. DeBrakeleer_2010, Couch_2015, Weber-Lassalle_2019). These data indicate that the variant is very likely to be associated with disease. The variant has also been found in at least one patient with pancreatic cancer (Smith_2016). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Malignant tumor of breast Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant interpreted as Pathogenic and reported on 09-21-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs587780024; hg19: chr2-215595181;