NM_000465.4(BARD1):c.144G>A (p.Leu48=) AND not provided

Germline classification:: Benign/Likely benign (3 submissions)
Last evaluated:: May 19, 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:: RCV000587640.9

Allele description [Variation Report for NM_000465.4(BARD1):c.144G>A (p.Leu48=)]

NM_000465.4(BARD1):c.144G>A (p.Leu48=)

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.144G>A (p.Leu48=)

HGVS:

NC_000002.12:g.214809426C>T
NG_012047.3:g.5286G>A
NM_000465.4:c.144G>AMANE SELECT
NM_001282543.2:c.144G>A
NM_001282545.2:c.144G>A
NM_001282548.2:c.144G>A
NM_001282549.2:c.144G>A
NP_000456.2:p.Leu48=
NP_001269472.1:p.Leu48=
NP_001269474.1:p.Leu48=
NP_001269477.1:p.Leu48=
NP_001269478.1:p.Leu48=
LRG_297t1:c.144G>A
LRG_297:g.5286G>A
LRG_297p1:p.Leu48=
NC_000002.11:g.215674150C>T
NG_012047.2:g.5279G>A
NM_000465.2:c.144G>A
NM_000465.3:c.144G>A
NR_104212.2:n.258G>A
NR_104215.2:n.258G>A
NR_104216.2:n.258G>A
p.L48L

Links:

dbSNP: rs151168457

NCBI 1000 Genomes Browser:

rs151168457

Molecular consequence:

NR_104212.2:n.258G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_104215.2:n.258G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_104216.2:n.258G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_000465.4:c.144G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001282543.2:c.144G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001282545.2:c.144G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001282548.2:c.144G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001282549.2:c.144G>A - synonymous variant - [Sequence Ontology: SO:0001819]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000293279	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely benign (Feb 12, 2021)	germline	clinical testing	Citation Link,
SCV000696743	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (May 15, 2017)	germline	clinical testing	LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000887587	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Benign (May 19, 2023)	unknown	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

SCV000293279

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely benign
(Feb 12, 2021)

germline

clinical testing

Citation Link,

SCV000696743

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(May 15, 2017)

germline

clinical testing

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV000887587

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Benign
(May 19, 2023)

unknown

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	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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

Details of each submission

From GeneDx, SCV000293279.11

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

Description

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this variant does not alter splicing

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696743.1

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

Description

Variant summary: The BARD1 c.144G>A (p.Leu48Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. Mutation taster predicts a damaging outcome for this variant and ESE finder predicts that this variant may abrogate the binding sites for SRp55 and SF2/ASF. However, 5/5 splice prediction tools predict no significant impact on normal splicing. These predictions have not been confirmed by functional studies. The variant of interest has been found in large and broad control population from ExAC in 13/107980 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.001326 (10/7544). This frequency is about 6 times the estimated maximal expected allele frequency of a pathogenic BARD1 variant (0.0002188), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In addition, this variant was found to be co-occurring with a pathogenic variant ATM c.7913G>A (p.Trp2638X) in an internal sample, further supporting benign outcome. In ClinVar, while two clinical laboratories classify it as likely benign, one classifies it as uncertain significance. The variant of interest has not been reported in affected individuals via publications. Taken together, this variant is currently classified as Likely 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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000887587.3

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

Last Updated: Sep 29, 2024

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