NM_000465.4(BARD1):c.716T>A (p.Leu239Gln) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 11, 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:: RCV000212121.13

Allele description [Variation Report for NM_000465.4(BARD1):c.716T>A (p.Leu239Gln)]

NM_000465.4(BARD1):c.716T>A (p.Leu239Gln)

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.716T>A (p.Leu239Gln)

Other names:

p.L239Q:CTG>CAG

HGVS:

NC_000002.12:g.214781158A>T
NG_012047.3:g.33554T>A
NM_000465.4:c.716T>AMANE SELECT
NM_001282543.2:c.659T>A
NM_001282545.2:c.215+15903T>A
NM_001282548.2:c.158+28254T>A
NM_001282549.2:c.364+11139T>A
NP_000456.2:p.Leu239Gln
NP_001269472.1:p.Leu220Gln
LRG_297t1:c.716T>A
LRG_297:g.33554T>A
LRG_297p1:p.Leu239Gln
NC_000002.11:g.215645882A>T
NG_012047.2:g.33547T>A
NM_000465.2:c.716T>A
NM_000465.3:c.716T>A
NR_104212.2:n.681T>A
NR_104215.2:n.624T>A
p.L239Q

Protein change:

L220Q

Links:

dbSNP: rs200359745

NCBI 1000 Genomes Browser:

rs200359745

Molecular consequence:

NM_001282545.2:c.215+15903T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001282548.2:c.158+28254T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001282549.2:c.364+11139T>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000465.4:c.716T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001282543.2:c.659T>A - missense variant - [Sequence Ontology: SO:0001583]
NR_104212.2:n.681T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_104215.2:n.624T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000149551	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Sep 11, 2023)	germline	clinical testing	Citation Link,
SCV000887602	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Jun 15, 2023)	unknown	clinical testing	PubMed (11) [See all records that cite these PMIDs] 32039725, 31275557, 33471991, 31159747, 27720647, 26787654, 30925164, 26976419, 35264596, 35595798, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000149551

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Sep 11, 2023)

germline

clinical testing

Citation Link,

SCV000887602

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Uncertain significance
(Jun 15, 2023)

unknown

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Germline variants in DNA repair genes associated with hereditary breast and ovarian cancer syndrome: analysis of a 21 gene panel in the Brazilian population.

da Costa E Silva Carvalho S, Cury NM, Brotto DB, de Araujo LF, Rosa RCA, Texeira LA, Plaça JR, Marques AA, Peronni KC, Ruy PC, Molfetta GA, Moriguti JC, Carraro DM, Palmero EI, Ashton-Prolla P, de Faria Ferraz VE, Silva WA Jr.

BMC Med Genomics. 2020 Feb 10;13(1):21. doi: 10.1186/s12920-019-0652-y.

PubMed [citation]

PMID:: 32039725
PMCID:: PMC7011249

Pan-cancer repository of validated natural and cryptic mRNA splicing mutations.

Shirley BC, Mucaki EJ, Rogan PK.

Version 3. F1000Res. 2018 [revised 2019 Sep 6];7:1908. doi: 10.12688/f1000research.17204.3.

PubMed [citation]

PMID:: 31275557
PMCID:: PMC6544075

See all PubMed Citations (11)

Details of each submission

From GeneDx, SCV000149551.19

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

Description

In silico analysis supports a deleterious effect on splicing; In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies are inconclusive: homology-directed repair activity comparable to wild type, but may cause abnormal splicing (Shirley et al., 2018; Adamovich et al., 2019); Observed in individuals with personal or family history of breast or other cancers and also in unaffected controls (Tung et al., 2016; Tsaousis et al., 2019; da Costa e Silva Carvalho et al., 2020; Dorling et al., 2021; Guindalini et al., 2022); This variant is associated with the following publications: (PMID: 32039725, 26976419, 26787654, 27720647, 30925164, 31159747, 31275557, 35595798, 33471991, 35264596)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000887602.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

In the published literature, this variant has been reported in individuals with breast cancer (PMID: 26976419 (2016), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BARD1), 35264596 (2022)), as well as unaffected individuals (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BARD1)). A functional study reported that this variant has proficient homology-directed repair (HDR) activity (PMID: 30925164 (2019)). The frequency of this variant in the general population, 0.00016 (19/118622 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on BARD1 mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Based on the available information, we are unable to determine the clinical significance of this variant.

#	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: Jan 13, 2025

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