NM_000465.4(BARD1):c.2229dup (p.Asn744Ter) AND Familial cancer of breast

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Dec 1, 2023
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:: RCV000531970.11

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:: Familial cancer of breast
Synonyms:: Breast cancer, familial; Hereditary breast cancer
Identifiers:: MONDO: MONDO:0016419; MedGen: C0346153; OMIM: 114480

Recent activity

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carboxy terminal-processing peptidase [Chryseobacterium suipulveris]
carboxy terminal-processing peptidase [Chryseobacterium suipulveris]
gi|2216360825|gnl|PRJNA820572|MTP09 5|gb|UOE41121.1|

Protein
LOC117416617 [Acipenser ruthenus]
LOC117416617 [Acipenser ruthenus]
Gene ID:117416617

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000633021	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 1, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17848578, 30925164, 28492532
SCV004044955	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Pathogenic (May 25, 2023)	unknown	clinical testing	Citation Link,
SCV004217310	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 5, 2022)	unknown	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

SCV000633021

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 1, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV004044955

Myriad Genetics, Inc.

criteria provided, single submitter

(Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))

Pathogenic
(May 25, 2023)

unknown

clinical testing

Citation Link,

SCV004217310

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Dec 5, 2022)

unknown

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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Structural requirements for the BARD1 tumor suppressor in chromosomal stability and homology-directed DNA repair.

Laufer M, Nandula SV, Modi AP, Wang S, Jasin M, Murty VV, Ludwig T, Baer R.

J Biol Chem. 2007 Nov 23;282(47):34325-33. Epub 2007 Sep 11.

PubMed [citation]

PMID:: 17848578

Functional analysis of BARD1 missense variants in homology-directed repair and damage sensitivity.

Adamovich AI, Banerjee T, Wingo M, Duncan K, Ning J, Martins Rodrigues F, Huang KL, Lee C, Chen F, Ding L, Parvin JD.

PLoS Genet. 2019 Mar;15(3):e1008049. doi: 10.1371/journal.pgen.1008049.

PubMed [citation]

PMID:: 30925164
PMCID:: PMC6457558

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000633021.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change creates a premature translational stop signal (p.Asn744*) in the BARD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 34 amino acid(s) of the BARD1 protein. This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 460740). This variant disrupts the C-terminal BRCT domain of BARD1 protein, which is required for chromosome stability and homology-directed repair (PMID: 17848578). A different variant (p.Val767fs) that lies downstream of this variant has been reported to affect BARD1 protein function (PMID: 30925164), this suggests that disruption of this region of the protein is causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been 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

From Myriad Genetics, Inc., SCV004044955.2

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

Description

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

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

From Baylor Genetics, SCV004217310.1

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

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

Last Updated: Sep 29, 2024

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