NM_000465.4(BARD1):c.216-1G>A AND Familial cancer of breast

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: May 18, 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:: RCV001065792.8

Allele description [Variation Report for NM_000465.4(BARD1):c.216-1G>A]

NM_000465.4(BARD1):c.216-1G>A

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.216-1G>A

HGVS:

NC_000002.12:g.214792446C>T
NG_012047.3:g.22266G>A
NM_000465.4:c.216-1G>AMANE SELECT
NM_001282543.2:c.159-1G>A
NM_001282545.2:c.215+4615G>A
NM_001282548.2:c.158+16966G>A
NM_001282549.2:c.216-1G>A
LRG_297t1:c.216-1G>A
LRG_297:g.22266G>A
NC_000002.11:g.215657170C>T
NM_000465.2:c.216-1G>A
NM_000465.3:c.216-1G>A

Links:

dbSNP: rs876658905

NCBI 1000 Genomes Browser:

rs876658905

Molecular consequence:

NM_001282545.2:c.215+4615G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001282548.2:c.158+16966G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000465.4:c.216-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001282543.2:c.159-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001282549.2:c.216-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001230776	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 28, 2019)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16199547, 20077502, 21344236, 28492532
SCV004044376	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Likely pathogenic (May 18, 2023)	unknown	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001230776

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 28, 2019)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV004044376

Myriad Genetics, Inc.

criteria provided, single submitter

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

Likely pathogenic
(May 18, 2023)

unknown

clinical testing

Citation Link

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

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

Cancer predisposing missense and protein truncating BARD1 mutations in non-BRCA1 or BRCA2 breast cancer families.

De Brakeleer S, De Grève J, Loris R, Janin N, Lissens W, Sermijn E, Teugels E.

Hum Mutat. 2010 Mar;31(3):E1175-85. doi: 10.1002/humu.21200.

PubMed [citation]

PMID:: 20077502

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV001230776.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BARD1 are known to be pathogenic (PMID: 20077502, 21344236). This variant has not been reported in the literature in individuals with BARD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 231019). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 2 of the BARD1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.

#	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., SCV004044376.2

#	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 likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.

#	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: May 1, 2024

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