VCV000419682.20 - ClinVar

NM_000465.4(BARD1):c.1314+5G>T

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(6)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000465.4(BARD1):c.1314+5G>T

Variation ID: 419682 Accession: VCV000419682.20

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q35 2: 214780555 (GRCh38) [ NCBI UCSC ] 2: 215645279 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 29, 2017	May 1, 2024	Jan 5, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000465.4:c.1314+5G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001282543.2:c.1257+5G>T		intron variant
NM_001282545.2:c.215+16506G>T		intron variant
NM_001282548.2:c.159-28000G>T		intron variant
NM_001282549.2:c.364+11742G>T		intron variant
NC_000002.12:g.214780555C>A
NC_000002.11:g.215645279C>A
NG_012047.3:g.34157G>T
LRG_297:g.34157G>T
LRG_297t1:c.1314+5G>T

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000002.12:214780554:C:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Links

ClinGen: CA16617443 dbSNP: rs868089048 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
BARD1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	4007	4063

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Familial cancer of breast	Uncertain significance (1)	criteria provided, single submitter	Jan 5, 2024	RCV000687118.9
not provided	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Nov 3, 2021	RCV000758764.7
Hereditary cancer-predisposing syndrome	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Sep 21, 2023	RCV001010920.7

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (May 24, 2016)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000567651.4 First in ClinVar: Apr 29, 2017 Last updated: Apr 17, 2019	Comment: This variant is denoted BARD1 c.1314+5G>T or IVS4+5G>T and consists of a G>T nucleotide substitution at the +5 position of intron 4 of the BARD1 … (more) This variant is denoted BARD1 c.1314+5G>T or IVS4+5G>T and consists of a G>T nucleotide substitution at the +5 position of intron 4 of the BARD1 gene. Multiple in silico models predict this variant to weaken the nearby natural splicing donor site, and to possibly cause abnormal gene splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. This variant has not, to our knowledge, been published in the literature as either a mutation or a benign polymorphism. The guanine (G) nucleotide that is altered is conserved across species. Based on the currently available information, we consider BARD1 c.1314+5G>T to be a variant of unknown significance. (less)
Uncertain significance (Jul 21, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV001341177.2 First in ClinVar: Jun 22, 2020 Last updated: Jun 19, 2021	Comment: This variant causes a G to T nucleotide substitution at the +5 position of intron 4 of the BARD1 gene. Splice site prediction tools predict … (more) This variant causes a G to T nucleotide substitution at the +5 position of intron 4 of the BARD1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. However, this prediction has not been confirmed in published RNA studies. To our knowledge, 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. (less)
Uncertain significance (Aug 15, 2018)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000887583.2 First in ClinVar: Mar 14, 2019 Last updated: Jan 01, 2022
Uncertain significance (Nov 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002009157.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023
Uncertain significance (Jan 05, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial cancer of breast Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000814670.6 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 28492532‚ 17576681‚ 9536098 Comment: This sequence change falls in intron 4 of the BARD1 gene. It does not directly change the encoded amino acid sequence of the BARD1 protein. … (more) This sequence change falls in intron 4 of the BARD1 gene. It does not directly change the encoded amino acid sequence of the BARD1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). 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: 419682). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. (less)
Uncertain significance (Sep 21, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV001171185.4 First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024	Comment: The c.1314+5G>T intronic variant results from a G to T substitution 5 nucleotides after coding exon 4 in the BARD1 gene. This nucleotide position is … (more) The c.1314+5G>T intronic variant results from a G to T substitution 5 nucleotides after coding exon 4 in the BARD1 gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)

Comment:

This variant is denoted BARD1 c.1314+5G>T or IVS4+5G>T and consists of a G>T nucleotide substitution at the +5 position of intron 4 of the BARD1 gene. Multiple in silico models predict this variant to weaken the nearby natural splicing donor site, and to possibly cause abnormal gene splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. This variant has not, to our knowledge, been published in the literature as either a mutation or a benign polymorphism. The guanine (G) nucleotide that is altered is conserved across species. Based on the currently available information, we consider BARD1 c.1314+5G>T to be a variant of unknown significance.

Comment:

This variant causes a G to T nucleotide substitution at the +5 position of intron 4 of the BARD1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. However, this prediction has not been confirmed in published RNA studies. To our knowledge, 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.

Comment:

This sequence change falls in intron 4 of the BARD1 gene. It does not directly change the encoded amino acid sequence of the BARD1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). 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: 419682). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.

Comment:

The c.1314+5G>T intronic variant results from a G to T substitution 5 nucleotides after coding exon 4 in the BARD1 gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.	Buratti E	Nucleic acids research	2007	PMID: 17576681
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098

Text-mined citations for rs868089048 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000465.4(BARD1):c.1314+5G>T

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs868089048 ...