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

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Aug 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:: RCV000779824.10

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:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000916646	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Oct 10, 2019)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 26787654, 26976419, 30925164, 31159747, 31275557 Citation Link,
SCV002071335	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 25, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002760251	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 15, 2023)	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

SCV000916646

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Oct 10, 2019)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV002071335

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 25, 2019)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002760251

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 15, 2023)

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	no	not provided	not provided	not provided	not provided	not provided	clinical testing
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

Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer.

Tung N, Lin NU, Kidd J, Allen BA, Singh N, Wenstrup RJ, Hartman AR, Winer EP, Garber JE.

J Clin Oncol. 2016 May 1;34(13):1460-8. doi: 10.1200/JCO.2015.65.0747. Epub 2016 Mar 14.

PubMed [citation]

PMID:: 26976419
PMCID:: PMC4872307

See all PubMed Citations (6)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000916646.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: BARD1 c.716T>A (p.Leu239Gln) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 217412 control chromosomes, predominantly at a frequency of 0.00017 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is somewhat lower than the expected maximum for a pathogenic variant in BARD1 causing Hereditary Breast and Ovarian Cancer (0.00017 vs 0.00025), allowing no clear conclusions about variant significance. c.716T>A has been reported in the literature in individuals with a personal or family history of breast and/or ovarian cancer (e.g. Tung_2016, Tsaousis_2019, Adamovich_2019) and other tumor phenotypes (Adamovich_2019); however without strong evidence for causality. These reports therefore do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. One publication reported experimental evidence demonstrating that the variant protein is fully functional in homology-directed DNA repair (HDR) (Adamovich_2019). Ten other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation: nine laboratories cited the variant as uncertain significance, while one cited the variant as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

#	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 Genetic Services Laboratory, University of Chicago, SCV002071335.1

#	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	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV002760251.3

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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Relating variation to medicine