NM_000465.4(BARD1):c.716T>A (p.Leu239Gln) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: May 14, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000115642.22

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)

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
SCV000185658	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (May 14, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 26787654, 26976419, 30925164, 31159747, 31275557, 32039725 Citation Link,
SCV000803145	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 23, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000821897	GeneKor MSA	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 1, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000910706	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (May 19, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002529646	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Jun 17, 2021)	germline	curation	PubMed (6) [See all records that cite these PMIDs] 26976419, 31159747, 32039725, 33471991, 31275557, 30925164 Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	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, curation

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

See all PubMed Citations (8)

Details of each submission

From Ambry Genetics, SCV000185658.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

The p.L239Q variant (also known as c.716T>A), located in coding exon 4 of the BARD1 gene, results from a T to A substitution at nucleotide position 716. The leucine at codon 239 is replaced by glutamine, an amino acid with dissimilar properties. This alteration has been reported in individuals with a personal or family history of breast and/or ovarian cancer (da Costa E Silva Carvalho S et al. BMC Med Genomics, 2020 02;13:21; Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535; Tung N et al. J. Clin. Oncol., 2016 May;34:1460-8; Young EL et al. J. Med. Genet., 2016 06;53:366-76). This alteration was found to be functional in a homology-directed DNA repair (HDR) assay (Adamovich AI et al. PLoS Genet., 2019 03;15:e1008049). RNA analyses have shown that this alteration leads to aberrant splicing by creating a new alternate donor site (Shirley BC et al. F1000Res, 2018 Dec;7:1908).This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration 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 Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C., SCV000803145.1

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

From GeneKor MSA, SCV000821897.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV000910706.1

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

From Sema4, Sema4, SCV002529646.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (6)

#	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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