NM_000465.4(BARD1):c.539_540del (p.Ser179_Tyr180insTer) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Feb 15, 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:: RCV000166193.11

Allele description [Variation Report for NM_000465.4(BARD1):c.539_540del (p.Ser179_Tyr180insTer)]

NM_000465.4(BARD1):c.539_540del (p.Ser179_Tyr180insTer)

Gene:

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

Variant type:

Microsatellite

Cytogenetic location:

2q35

Genomic location:

Preferred name:

NM_000465.4(BARD1):c.539_540del (p.Ser179_Tyr180insTer)

HGVS:

NC_000002.12:g.214781334AT[1]
NG_012047.3:g.33375AT[1]
NM_000465.2:c.539_540del
NM_000465.4:c.539_540delMANE SELECT
NM_001282543.2:c.482_483del
NM_001282545.2:c.215+15726_215+15727del
NM_001282548.2:c.158+28077_158+28078del
NM_001282549.2:c.364+10962_364+10963del
NP_000456.2:p.Ser179_Tyr180insTer
NP_001269472.1:p.Ser160_Tyr161insTer
LRG_297t1:c.539_540del
LRG_297:g.33375AT[1]
LRG_297p1:p.Ser179_Tyr180insTer
NC_000002.11:g.215646058AT[1]
NC_000002.11:g.215646058_215646059del
NM_000465.2:c.539_540delAT
NM_000465.3:c.539_540delAT
NM_000465.4:c.539_540del
NR_104212.2:n.502AT[1]
NR_104215.2:n.445AT[1]
p.Y180*

Links:

dbSNP: rs779427628

NCBI 1000 Genomes Browser:

rs779427628

Molecular consequence:

NM_001282545.2:c.215+15726_215+15727del - intron variant - [Sequence Ontology: SO:0001627]
NM_001282548.2:c.158+28077_158+28078del - intron variant - [Sequence Ontology: SO:0001627]
NM_001282549.2:c.364+10962_364+10963del - intron variant - [Sequence Ontology: SO:0001627]
NR_104212.2:n.502AT[1] - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_104215.2:n.445AT[1] - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_000465.4:c.539_540del - nonsense - [Sequence Ontology: SO:0001587]
NM_001282543.2:c.482_483del - 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
SCV000216970	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Feb 15, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28724667, 29922827 Citation Link,
SCV000908590	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	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

SCV000216970

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Feb 15, 2023)

germline

clinical testing

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

Citation Link,

SCV000908590

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

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

Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients.

Sun J, Meng H, Yao L, Lv M, Bai J, Zhang J, Wang L, Ouyang T, Li J, Wang T, Fan Z, Fan T, Lin B, Xie Y.

Clin Cancer Res. 2017 Oct 15;23(20):6113-6119. doi: 10.1158/1078-0432.CCR-16-3227. Epub 2017 Jul 19.

PubMed [citation]

PMID:: 28724667

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

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000216970.8

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

Description

The c.539_540delAT pathogenic mutation, located in coding exon 4 of the BARD1 gene, results from a deletion of two nucleotides at nucleotide positions 539 to 540, causing a translational frameshift with a predicted alternate stop codon (p.Y180*). This alteration was detected in a cohort of 8085 consecutive unselected Chinese breast cancer patients who underwent multi-gene panel testing (Sun J et al. Clin. Cancer Res., 2017 Oct;23:6113-6119) and was seen in 0/3030 cases of pancreatic cancer and 1/123136 controls from gnomAD (Hu C et al. JAMA, 2018 06;319:2401-2409). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

#	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, SCV000908590.3

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

Description

This variant deletes 2 nucleotides in exon 4 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 3/282036 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 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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