NM_000465.4(BARD1):c.159-1G>T AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jun 27, 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:: RCV000565922.16

Allele description [Variation Report for NM_000465.4(BARD1):c.159-1G>T]

NM_000465.4(BARD1):c.159-1G>T

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.159-1G>T

HGVS:

NC_000002.12:g.214797118C>A
NG_012047.3:g.17594G>T
NM_000465.4:c.159-1G>TMANE SELECT
NM_001282543.2:c.159-4673G>T
NM_001282545.2:c.159-1G>T
NM_001282548.2:c.158+12294G>T
NM_001282549.2:c.159-1G>T
LRG_297t1:c.159-1G>T
LRG_297:g.17594G>T
NC_000002.11:g.215661842C>A
NM_000465.2:c.159-1G>T
NM_000465.3:c.159-1G>T

Links:

dbSNP: rs879254139

NCBI 1000 Genomes Browser:

rs879254139

Molecular consequence:

NM_001282543.2:c.159-4673G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001282548.2:c.158+12294G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000465.4:c.159-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001282545.2:c.159-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001282549.2:c.159-1G>T - splice acceptor variant - [Sequence Ontology: SO:0001574]

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
SCV000660810	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Jun 27, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31036035, 31843900 Citation Link,
SCV000688135	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 9, 2021)	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

SCV000660810

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Jun 27, 2023)

germline

clinical testing

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

Citation Link,

SCV000688135

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 9, 2021)

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

Germline loss-of-function variants in the BARD1 gene are associated with early-onset familial breast cancer but not ovarian cancer.

Weber-Lassalle N, Borde J, Weber-Lassalle K, Horváth J, Niederacher D, Arnold N, Kaulfuß S, Ernst C, Paul VG, Honisch E, Klaschik K, Volk AE, Kubisch C, Rapp S, Lichey N, Altmüller J, Lepkes L, Pohl-Rescigno E, Thiele H, Nürnberg P, Larsen M, Richters L, et al.

Breast Cancer Res. 2019 Apr 29;21(1):55. doi: 10.1186/s13058-019-1137-9.

PubMed [citation]

PMID:: 31036035
PMCID:: PMC6489184

Characterization of splice-altering mutations in inherited predisposition to cancer.

Casadei S, Gulsuner S, Shirts BH, Mandell JB, Kortbawi HM, Norquist BS, Swisher EM, Lee MK, Goldberg Y, O'Connor R, Tan Z, Pritchard CC, King MC, Walsh T.

Proc Natl Acad Sci U S A. 2019 Dec 26;116(52):26798-26807. doi: 10.1073/pnas.1915608116. Epub 2019 Dec 16.

PubMed [citation]

PMID:: 31843900
PMCID:: PMC6936554

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000660810.7

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

Description

The c.159-1G>T intronic variant results from a G to T substitution one nucleotide upstream from coding exon 2 of the BARD1 gene. In one study, this alteration was detected in 1/4469 German breast cancer patients (Weber-Lassalle N et al. Breast Cancer Res., 2019 04;21:55). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). A published RNA study also identified abnormal splicing associated with this variant (Casadei S et al. Proc Natl Acad Sci U S A, 2019 Dec). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration 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

From Color Diagnostics, LLC DBA Color Health, SCV000688135.5

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

Description

This variant causes a G to T nucleotide substitution at the -1 position of intron 1 of the BARD1 gene. An RNA study has reported two aberrant transcripts found uniquely in carrier and absent in healthy control that are expected to produce absent or non-functional protein product (PMID: 31843900). This variant also has been reported in one individual each affected with breast and ovarian cancer (PMID: 31036035, 31843900). This variant has not been identified 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 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: May 12, 2024

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