rs386654966

chr2-214767531-CA-AGchr2-214767531-CA-TG

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_000465.4(BARD1):c.1518_1519delinsCT(p.Val507Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. HV506HM) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: -0.241

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BARD1	NM_000465.4	c.1518_1519delinsCT	p.Val507Leu	missense_variant	6/11	ENST00000260947.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BARD1	ENST00000260947.9	c.1518_1519delinsCT	p.Val507Leu	missense_variant	6/11	1	NM_000465.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 11, 2023	This missense variant replaces valine with leucine at codon 507 of the BARD1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 18, 2023	The c.1518_1519delTGinsCT variant, located in coding exon 6 of the BARD1 gene, results from an in-frame deletion of TG and insertion of CT at nucleotide positions 1518 to 1519. This results in the substitution of the valine residue for a leucine residue at codon 507, an amino acid with highly similar properties. This variant did not show significant association with early onset breast cancer in an Indonesian population (Panigoro SS et al. Asian Pac J Cancer Prev, 2021 Dec;22:3985-3991). In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). This amino acid position is not well conserved in available vertebrate species, and leucine is the reference amino acid in other vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 22, 2015

This variant is denoted BARD1 c.1518_1519delTGinsCT at the cDNA level. The normal sequence, with the bases that are deleted in braces and inserted in brackets, is GGCA[TG][CT]TGGA. This in frame deletion and insertion occurs on the same allele (in cis) and results in a synonymous change at codon 506 and the amino acid substitution of p.Val507Leu (V507L). Neither BARD1 c.1518_1519delTGinsCT nor BARD1 Val507Leu (by this or an alternate nucleotide change) have been published in the literature as pathogenic or benign, nor were they observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating they are not common benign variants in these populations. Regarding BARD1 Val507Leu, since Valine and Leucine share similar properties, this is considered a conservative amino acid substitution. It occurs at a position that is not conserved, with Leucine being the naturally occurring amino acid at this position in several mammals. In silico analyses predict that BARD1 Val507Leu is unlikely to alter protein structure or function. BARD1 c.1518_1519delTGinsCT is located within the ANK3 repeat (UniProt) and based on currently available information, we consider it to be a variant of uncertain significance. -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 29, 2023

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. This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 507 of the BARD1 protein (p.Val507Leu). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has not been reported in the literature in individuals affected with BARD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 419324). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jun 16, 2017

Variant summary: The BARD1 c.1518_1519delinsCT (p.Val507delinsLeu) variant involves the replacement of two adjacent non-conserved nucleotides leading to a missense change. 2/2 in silico tools predict a benign outcome for this variant. Variant c.1518T>C was found in 224884/276978 control chromosomes in gnomAD with MAF of 0.8119 supporting benign outcome; the variant c.1519G>T was found in 8/246146 control chromosomes in gnomAD, predominantly observed in the East Asian subpopulation at a frequency of 0.000424 (8/18860). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic BARD1 variant (0.0002188), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as likely benign until additional information becomes available. -

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: rs386654966; hg19: chr2-215632255;