NM_000465.4(BARD1):c.716T>A (p.Leu239Gln) AND Familial cancer of breast

Germline classification:: Conflicting interpretations of pathogenicity (7 submissions)
Last evaluated:: Dec 16, 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:: RCV000206495.23

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]

Observations:

Condition(s)

Name:: Familial cancer of breast
Synonyms:: BREAST CANCER, FAMILIAL; Hereditary breast cancer
Identifiers:: MONDO: MONDO:0016419; MedGen: C0346153; OMIM: 114480

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000261241	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 28, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 26976419, 31159747, 35595798, 30925164, 28492532
SCV000785164	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Uncertain significance (May 16, 2017)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Counsyl_Autosomal_Dominant_Disease_Classification_criteria_(2015)_v1.pdf, Citation Link,
SCV000837978	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Uncertain significance (Jul 2, 2018)	unknown	clinical testing	Citation Link,
SCV000895394	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 31, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002584573	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	criteria provided, single submitter (St. Jude Assertion Criteria 2020)	Uncertain significance (Aug 23, 2022)	germline	clinical testing	Citation Link,
SCV004019266	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Likely benign (Feb 24, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV005437108	KCCC/NGS Laboratory, Kuwait Cancer Control Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 16, 2024)	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	yes	1	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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations.

Tsaousis GN, Papadopoulou E, Apessos A, Agiannitopoulos K, Pepe G, Kampouri S, Diamantopoulos N, Floros T, Iosifidou R, Katopodi O, Koumarianou A, Markopoulos C, Papazisis K, Venizelos V, Xanthakis I, Xepapadakis G, Banu E, Eniu DT, Negru S, Stanculeanu DL, Ungureanu A, Ozmen V, et al.

BMC Cancer. 2019 Jun 3;19(1):535. doi: 10.1186/s12885-019-5756-4.

PubMed [citation]

PMID:: 31159747
PMCID:: PMC6547505

Apparent regional differences in the spectrum of BARD1 pathogenic variants in Spanish population and importance of copy number variants.

Benito-Sánchez B, Barroso A, Fernández V, Mercadillo F, Núñez-Torres R, Pita G, Pombo L, Morales-Chamorro R, Cano-Cano JM, Urioste M, González-Neira A, Osorio A.

Sci Rep. 2022 May 20;12(1):8547. doi: 10.1038/s41598-022-12480-2.

PubMed [citation]

PMID:: 35595798
PMCID:: PMC9122922

See all PubMed Citations (7)

PMC

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.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000261241.12

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

Description

This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 239 of the BARD1 protein (p.Leu239Gln). This variant is present in population databases (rs200359745, gnomAD 0.02%). This missense change has been observed in individual(s) with personal or family history of breast and/or ovarian cancer (PMID: 26976419, 31159747, 35595798). ClinVar contains an entry for this variant (Variation ID: 127746). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect BARD1 function (PMID: 30925164). Studies have shown that this missense change is associated with altered splicing resulting in multiple RNA products (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been 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

From Counsyl, SCV000785164.2

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

From Mendelics, SCV000837978.2

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

#	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

From Fulgent Genetics, Fulgent Genetics, SCV000895394.1

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

From St. Jude Molecular Pathology, St. Jude Children's Research Hospital, SCV002584573.1

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

Description

The BARD1 c.716T>A (p.Leu239Gln) missense change has a maximum subpopulation frequency of 0.016% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant has been reported in the literature in individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 26976419, 31159747, 32039725, 33471991). It has also been reported in one individual in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). Algorithms that predict the impact of sequence changes on splicing indicate that this change may affect splicing. RNA studies indicate that this variant strengthens a cryptic splice within exon 4 of the BARD1 gene and causes leaky splicing (PMID: 31275557). The in silico tool REVEL predicts a benign effect on protein function and functional analysis indicates that this variant has homology-directed repair (HDR) comparable to the wild-type (PMID: 30925164). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as 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

From Myriad Genetics, Inc., SCV004019266.1

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

Description

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].

#	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

From KCCC/NGS Laboratory, Kuwait Cancer Control Center, SCV005437108.1

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

Description

This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 239 of the BARD1 protein (p.Leu239Gln). This variant is present in population databases (rs200359745, gnomAD 0.02%). This amino acid position is poorly conserved. This missense change has been observed in individual(s) with personal or family history of breast and/or ovarian cancer (PMID: 26976419, 31159747, 35595798). ClinVar contains an entry for this variant (Variation ID: 127746). In addition, this alteration is predicted to be tolerated by in silico analysis. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been 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	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Jan 13, 2025

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