NM_000465.4(BARD1):c.57G>T (p.Glu19Asp) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 8, 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:: RCV001024548.7

Allele description [Variation Report for NM_000465.4(BARD1):c.57G>T (p.Glu19Asp)]

NM_000465.4(BARD1):c.57G>T (p.Glu19Asp)

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.57G>T (p.Glu19Asp)

HGVS:

NC_000002.12:g.214809513C>A
NG_012047.3:g.5199G>T
NM_000465.4:c.57G>TMANE SELECT
NM_001282543.2:c.57G>T
NM_001282545.2:c.57G>T
NM_001282548.2:c.57G>T
NM_001282549.2:c.57G>T
NP_000456.2:p.Glu19Asp
NP_001269472.1:p.Glu19Asp
NP_001269474.1:p.Glu19Asp
NP_001269477.1:p.Glu19Asp
NP_001269478.1:p.Glu19Asp
LRG_297t1:c.57G>T
LRG_297:g.5199G>T
LRG_297p1:p.Glu19Asp
NC_000002.11:g.215674237C>A
NG_012047.2:g.5192G>T
NM_000465.2:c.57G>T
NM_000465.3:c.57G>T
NR_104212.2:n.171G>T
NR_104215.2:n.171G>T
NR_104216.2:n.171G>T

Protein change:

E19D

Links:

dbSNP: rs730881406

NCBI 1000 Genomes Browser:

rs730881406

Molecular consequence:

NM_000465.4:c.57G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282543.2:c.57G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282545.2:c.57G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282548.2:c.57G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282549.2:c.57G>T - missense variant - [Sequence Ontology: SO:0001583]
NR_104212.2:n.171G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_104215.2:n.171G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_104216.2:n.171G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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

Recent activity

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Mus musculus homeobox B13 (Hoxb13), mRNA
Mus musculus homeobox B13 (Hoxb13), mRNA
gi|1344169057|ref|NM_008267.4|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001186580	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (May 8, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26787654, 33471991 Citation Link,
SCV002053193	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 8, 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

SCV001186580

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(May 8, 2024)

germline

clinical testing

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

Citation Link,

SCV002053193

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 8, 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

Multigene testing of moderate-risk genes: be mindful of the missense.

Young EL, Feng BJ, Stark AW, Damiola F, Durand G, Forey N, Francy TC, Gammon A, Kohlmann WK, Kaphingst KA, McKay-Chopin S, Nguyen-Dumont T, Oliver J, Paquette AM, Pertesi M, Robinot N, Rosenthal JS, Vallee M, Voegele C, Hopper JL, Southey MC, Andrulis IL, et al.

J Med Genet. 2016 Jun;53(6):366-76. doi: 10.1136/jmedgenet-2015-103398. Epub 2016 Jan 19.

PubMed [citation]

PMID:: 26787654
PMCID:: PMC4893078

Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.

Breast Cancer Association Consortium., Dorling L, Carvalho S, Allen J, González-Neira A, Luccarini C, Wahlström C, Pooley KA, Parsons MT, Fortuno C, Wang Q, Bolla MK, Dennis J, Keeman R, Alonso MR, Álvarez N, Herraez B, Fernandez V, Núñez-Torres R, Osorio A, Valcich J, Li M, et al.

N Engl J Med. 2021 Feb 4;384(5):428-439. doi: 10.1056/NEJMoa1913948. Epub 2021 Jan 20.

PubMed [citation]

PMID:: 33471991
PMCID:: PMC7611105

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV001186580.5

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

Description

The p.E19D variant (also known as c.57G>T), located in coding exon 1 of the BARD1 gene, results from a G to T substitution at nucleotide position 57. The glutamic acid at codon 19 is replaced by aspartic acid, an amino acid with highly similar properties. This variant was reported in 0/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med 2021 02;384:428-439). This variant was also reported in a study of 1297 cases of early-onset breast cancer and 1121 controls (Young EL et al. J Med Genet, 2016 Jun;53:366-76). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

#	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, SCV002053193.1

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

Description

This missense variant replaces glutamic acid with aspartic acid at codon 19 of the BARD1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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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