NM_000465.4(BARD1):c.55G>T (p.Glu19Ter) AND Familial cancer of breast

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Apr 24, 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:: RCV000458694.24

Allele description [Variation Report for NM_000465.4(BARD1):c.55G>T (p.Glu19Ter)]

NM_000465.4(BARD1):c.55G>T (p.Glu19Ter)

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.55G>T (p.Glu19Ter)

HGVS:

NC_000002.12:g.214809515C>A
NG_012047.3:g.5197G>T
NM_000465.4:c.55G>TMANE SELECT
NM_001282543.2:c.55G>T
NM_001282545.2:c.55G>T
NM_001282548.2:c.55G>T
NM_001282549.2:c.55G>T
NP_000456.2:p.Glu19Ter
NP_001269472.1:p.Glu19Ter
NP_001269474.1:p.Glu19Ter
NP_001269477.1:p.Glu19Ter
NP_001269478.1:p.Glu19Ter
LRG_297t1:c.55G>T
LRG_297:g.5197G>T
LRG_297p1:p.Glu19Ter
NC_000002.11:g.215674239C>A
NG_012047.2:g.5190G>T
NM_000465.2:c.55G>T
NM_000465.3:c.55G>T
NR_104212.2:n.169G>T
NR_104215.2:n.169G>T
NR_104216.2:n.169G>T

Protein change:

E19*

Links:

dbSNP: rs752514155

NCBI 1000 Genomes Browser:

rs752514155

Molecular consequence:

NR_104212.2:n.169G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_104215.2:n.169G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_104216.2:n.169G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_000465.4:c.55G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001282543.2:c.55G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001282545.2:c.55G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001282548.2:c.55G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001282549.2:c.55G>T - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000545608	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 25, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20077502, 21344236, 28492532
SCV000914897	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020)	Likely pathogenic (Apr 24, 2024)	unknown	clinical testing	Citation Link,
SCV001361542	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Jul 10, 2019)	germline	clinical testing	Citation Link,
SCV004044201	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Pathogenic (May 17, 2023)	unknown	clinical testing	Citation Link,
SCV004217175	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 13, 2024)	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	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Cancer predisposing BARD1 mutations in breast-ovarian cancer families.

Ratajska M, Antoszewska E, Piskorz A, Brozek I, Borg Å, Kusmierek H, Biernat W, Limon J.

Breast Cancer Res Treat. 2012 Jan;131(1):89-97. doi: 10.1007/s10549-011-1403-8. Epub 2011 Feb 23.

PubMed [citation]

PMID:: 21344236

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000545608.10

#	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.Glu19*) in the BARD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BARD1 are known to be pathogenic (PMID: 20077502, 21344236). This variant is present in population databases (rs752514155, gnomAD 0.02%). 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: 233594). For these reasons, this variant has been classified as 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 Illumina Laboratory Services, Illumina, SCV000914897.2

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

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001361542.1

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

Description

Variant summary: BARD1 c.55G>T (p.Glu19X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2.8e-05 in 215878 control chromosomes. To our knowledge, no occurrence of c.55G>T in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. At-least one co-occurrence with other pathogenic variant has been reported (BRCA1 c.45delT, p.Asn16MetfsX7) at our laboratory. Six clinical diagnostic laboratories (Pathogenic n=5; VUS n=1) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was 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., SCV004044201.2

#	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, SCV004217175.2

#	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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