VCV001784241.3 - ClinVar

NM_000465.4(BARD1):c.2001+2T>C

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.

(2)

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.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000465.4(BARD1):c.2001+2T>C

Variation ID: 1784241 Accession: VCV001784241.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q35 2: 214730409 (GRCh38) [ NCBI UCSC ] 2: 215595133 (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	Nov 29, 2022	May 1, 2024	Dec 16, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000465.4:c.2001+2T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_000465.3:c.2001+2T>C
NM_001282543.2:c.1944+2T>C		splice donor
NM_001282545.2:c.648+2T>C		splice donor
NM_001282548.2:c.591+2T>C		splice donor
NM_001282549.2:c.462+2T>C		splice donor
NC_000002.12:g.214730409A>G
NC_000002.11:g.215595133A>G
NG_012047.3:g.84303T>C
LRG_297:g.84303T>C
LRG_297t1:c.2001+2T>C

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000002.12:214730408:A:G

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.

Links

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.
Hereditary cancer-predisposing syndrome	Likely pathogenic (1)	criteria provided, single submitter	Nov 28, 2017	RCV002417178.2
not provided	Uncertain significance (1)	criteria provided, single submitter	Dec 16, 2022	RCV003477000.1

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 (Dec 16, 2022)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV004222388.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Comment: This variant disrupts a canonical splice-donor site in the second to last exon, but may not result in nonsense mediated decay. To the best of … (more) This variant disrupts a canonical splice-donor site in the second to last exon, but may not result in nonsense mediated decay. To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000004 (1/251366 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
Likely pathogenic (Nov 28, 2017)	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: SCV002719445.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: The c.2001+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 10 in the BARD1 gene. This nucleotide position is … (more) The c.2001+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 10 in the BARD1 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or transcript; however, the mRNA may escape nonsense mediated decay (NMD) since premature termination codons located either in the last exon or within 50-55 nucleotides upstream of the 3'-most exon-exon junction usually fail to elicit NMD (Maquat LE et al. Nat. Rev. Mol. Cell Biol. 2004 Feb; 5(2):89-99). However, the c.2001+2T>C alteration is located 5’ to the BARD1 BRCT domain (residues 568-777), which has been described as similar to those of the BRCA1 gene, and may be important for ligand binding (Birrane G et al. Biochemistry 2007 Jul; 46(26):7706-12). Further, an additional pathogenic mutation in the BARD1 gene, c.2148_2149delCA, is located 3’ to this alteration and has been described in a patient diagnosed with fallopian tube cancer at age 53 (Walsh, T el al. Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18032-7). Based on the available evidence, c.2001+2T>C is interpreted as likely pathogenic. (less)

Comment:

This variant disrupts a canonical splice-donor site in the second to last exon, but may not result in nonsense mediated decay. To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000004 (1/251366 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.

Comment:

The c.2001+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 10 in the BARD1 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or transcript; however, the mRNA may escape nonsense mediated decay (NMD) since premature termination codons located either in the last exon or within 50-55 nucleotides upstream of the 3'-most exon-exon junction usually fail to elicit NMD (Maquat LE et al. Nat. Rev. Mol. Cell Biol. 2004 Feb; 5(2):89-99). However, the c.2001+2T>C alteration is located 5’ to the BARD1 BRCT domain (residues 568-777), which has been described as similar to those of the BRCA1 gene, and may be important for ligand binding (Birrane G et al. Biochemistry 2007 Jul; 46(26):7706-12). Further, an additional pathogenic mutation in the BARD1 gene, c.2148_2149delCA, is located 3’ to this alteration and has been described in a patient diagnosed with fallopian tube cancer at age 53 (Walsh, T el al. Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18032-7). Based on the available evidence, c.2001+2T>C is interpreted as likely pathogenic.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for this variant ...

Record last updated May 01, 2024

ClinVar Genomic variation as it relates to human health

NM_000465.4(BARD1):c.2001+2T>C

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...