NM_000465.4(BARD1):c.2229dup (p.Asn744Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: May 30, 2024
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:: RCV001014816.10

Allele description [Variation Report for NM_000465.4(BARD1):c.2229dup (p.Asn744Ter)]

NM_000465.4(BARD1):c.2229dup (p.Asn744Ter)

Gene:

BARD1:BRCA1 associated RING domain 1 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

2q35

Genomic location:

Preferred name:

NM_000465.4(BARD1):c.2229dup (p.Asn744Ter)

HGVS:

NC_000002.12:g.214728781dup
NG_012047.3:g.85931dup
NM_000465.4:c.2229dupMANE SELECT
NM_001282543.2:c.2172dup
NM_001282545.2:c.876dup
NM_001282548.2:c.819dup
NM_001282549.2:c.690dup
NP_000456.2:p.Asn744Ter
NP_001269472.1:p.Asn725Ter
NP_001269474.1:p.Asn293Ter
NP_001269477.1:p.Asn274Ter
NP_001269478.1:p.Asn231Ter
LRG_297t1:c.2229dup
LRG_297:g.85931dup
LRG_297p1:p.Asn744Ter
NC_000002.11:g.215593504_215593505insA
NC_000002.11:g.215593505dup
NG_012047.2:g.85924dup
NM_000465.2:c.2229dupT
NM_000465.3:c.2229dup
NM_000465.3:c.2229dupT
NR_104212.2:n.2194dup
NR_104215.2:n.2137dup
NR_104216.2:n.1393dup

Protein change:

N231*

Links:

dbSNP: rs1259296823

NCBI 1000 Genomes Browser:

rs1259296823

Molecular consequence:

NR_104212.2:n.2194dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_104215.2:n.2137dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_104216.2:n.1393dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_000465.4:c.2229dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001282543.2:c.2172dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001282545.2:c.876dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001282548.2:c.819dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001282549.2:c.690dup - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001175575	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (May 30, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29922827, 32720237 Citation Link,
SCV001351400	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 15, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001175575

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(May 30, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV001351400

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 15, 2020)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer.

Hu C, Hart SN, Polley EC, Gnanaolivu R, Shimelis H, Lee KY, Lilyquist J, Na J, Moore R, Antwi SO, Bamlet WR, Chaffee KG, DiCarlo J, Wu Z, Samara R, Kasi PM, McWilliams RR, Petersen GM, Couch FJ.

JAMA. 2018 Jun 19;319(23):2401-2409. doi: 10.1001/jama.2018.6228.

PubMed [citation]

PMID:: 29922827
PMCID:: PMC6092184

Racial and Ethnic Disparities in Genetic Testing at a Hereditary Breast and Ovarian Cancer Center.

Chapman-Davis E, Zhou ZN, Fields JC, Frey MK, Jordan B, Sapra KJ, Chatterjee-Paer S, Carlson AD, Holcomb KM.

J Gen Intern Med. 2021 Jan;36(1):35-42. doi: 10.1007/s11606-020-06064-x. Epub 2020 Jul 27.

PubMed [citation]

PMID:: 32720237
PMCID:: PMC7859010

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV001175575.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The c.2229dupT variant, located in coding exon 11 of the BARD1 gene, results from a duplication of T at nucleotide position 2229, causing a translational frameshift with a predicted alternate stop codon (p.N744*). 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 34 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). Another truncating alteration downstream, p.V767fs*4 (c.2300_2301delTG), was found to be non-functional in a homology-directed DNA repair through functional studies (Adamovich AI et al. PLoS Genet. 2019 03;15:e1008049). One study detected the p.N744* alteration in 0/3030 pancreatic cancer cases and 1/123136 population controls (Hu C et al. JAMA, 2018 06;319:2401-2409). This alteration was also identified in one Hispanic individual undergoing genetic assessment at a hereditary breast and ovarian cancer center (Chapman-Davis E et al. J Gen Intern Med, 2021 01;36:35-42).This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV001351400.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant inserts 1 nucleotide in exon 11 of the BARD1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been identified in 1/251318 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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