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NM_000465.4(BARD1):c.2267G>A (p.Trp756Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:
Likely pathogenic (2 submissions)
Last evaluated:
Oct 23, 2020
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV001179860.6

Allele description [Variation Report for NM_000465.4(BARD1):c.2267G>A (p.Trp756Ter)]

NM_000465.4(BARD1):c.2267G>A (p.Trp756Ter)

Gene:
BARD1:BRCA1 associated RING domain 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2q35
Genomic location:
Preferred name:
NM_000465.4(BARD1):c.2267G>A (p.Trp756Ter)
HGVS:
  • NC_000002.12:g.214728743C>T
  • NG_012047.3:g.85969G>A
  • NM_000465.4:c.2267G>AMANE SELECT
  • NM_001282543.2:c.2210G>A
  • NM_001282545.2:c.914G>A
  • NM_001282548.2:c.857G>A
  • NM_001282549.2:c.728G>A
  • NP_000456.2:p.Trp756Ter
  • NP_001269472.1:p.Trp737Ter
  • NP_001269474.1:p.Trp305Ter
  • NP_001269477.1:p.Trp286Ter
  • NP_001269478.1:p.Trp243Ter
  • LRG_297t1:c.2267G>A
  • LRG_297:g.85969G>A
  • LRG_297p1:p.Trp756Ter
  • NC_000002.11:g.215593467C>T
  • NG_012047.2:g.85962G>A
  • NM_000465.2:c.2267G>A
  • NM_000465.3:c.2267G>A
  • NR_104212.2:n.2232G>A
  • NR_104215.2:n.2175G>A
  • NR_104216.2:n.1431G>A
Protein change:
W243*
Links:
dbSNP: rs1358155595
NCBI 1000 Genomes Browser:
rs1358155595
Molecular consequence:
  • NR_104212.2:n.2232G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_104215.2:n.2175G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_104216.2:n.1431G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NM_000465.4:c.2267G>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001282543.2:c.2210G>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001282545.2:c.914G>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001282548.2:c.857G>A - nonsense - [Sequence Ontology: SO:0001587]
  • NM_001282549.2:c.728G>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001344649Color Diagnostics, LLC DBA Color Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(May 18, 2020) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002737941Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Oct 23, 2020) 		germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Phosphopeptide binding specificities of BRCA1 COOH-terminal (BRCT) domains.

Rodriguez M, Yu X, Chen J, Songyang Z.

J Biol Chem. 2003 Dec 26;278(52):52914-8. Epub 2003 Oct 24.

PubMed [citation]
PMID:
14578343
See all PubMed Citations (7)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001344649.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This variant changes 1 nucleotide in exon 11 of the BARD1 gene, creating a premature translation stop signal. While this variant is not expected to trigger nonsense-mediated decay, this variant is predicted to partially truncate the BRCT domain that facilitates protein-protein interaction involved in BARD1's role in DNA repair and tumor suppression (PMID: 17550235, 17848578, 26738429). This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251250 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 Likely Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Ambry Genetics, SCV002737941.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

The p.W756* variant (also known as c.2267G>A), located in coding exon 11 of the BARD1 gene, results from a G to A substitution at nucleotide position 2267. This changes the amino acid from a tryptophan to a stop codon within coding exon 11. Premature stop codons are typically deleterious in nature; however, this stop codon occurs at the 3' terminus of BARD1, is not expected to trigger nonsense-mediated mRNA decay, and removes only the last 22 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time; however, structural analysis suggests this alteration results in loss of a large part of a well-ordered C-terminal BRCT domain with destabilization of the structure, which could disrupt protein-protein interactions (Birrane G et al. Biochemistry. 2007 Jul; 46(26):7706-12; Feki A et al. Oncogene. 2005 May; 24(23):3726-36; Edwards RA et al. Biochemistry. 2008 Nov; 47(44):11446-56; Rodriguez M et al. J. Biol. Chem. 2003 Dec; 278(52):52914-8; Ambry internal data). In addition, this alteration impacts the BRCT domain of BARD1, which has been shown to be necessary for homology-directed DNA repair (Laufer M et al. J Biol Chem, 2007 Nov;282:34325-33, Adamovich AI et al. PLoS Genet, 2019 03;15:e1008049). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024