NM_000465.4(BARD1):c.33G>T (p.Gln11His) AND not provided

Germline classification:: Benign/Likely benign (10 submissions)
Last evaluated:: Mar 1, 2024
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:: RCV000587822.30

Allele description [Variation Report for NM_000465.4(BARD1):c.33G>T (p.Gln11His)]

NM_000465.4(BARD1):c.33G>T (p.Gln11His)

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.33G>T (p.Gln11His)

Other names:

p.Q11H:CAG>CAT

HGVS:

NC_000002.12:g.214809537C>A
NG_012047.3:g.5175G>T
NM_000465.4:c.33G>TMANE SELECT
NM_001282543.2:c.33G>T
NM_001282545.2:c.33G>T
NM_001282548.2:c.33G>T
NM_001282549.2:c.33G>T
NP_000456.2:p.Gln11His
NP_001269472.1:p.Gln11His
NP_001269474.1:p.Gln11His
NP_001269477.1:p.Gln11His
NP_001269478.1:p.Gln11His
LRG_297t1:c.33G>T
LRG_297:g.5175G>T
LRG_297p1:p.Gln11His
NC_000002.11:g.215674261C>A
NG_012047.2:g.5168G>T
NM_000465.2:c.33G>T
NM_000465.3:c.33G>T
NR_104212.2:n.147G>T
NR_104215.2:n.147G>T
NR_104216.2:n.147G>T
p.Q11H

Protein change:

Q11H

Links:

dbSNP: rs143914387

NCBI 1000 Genomes Browser:

rs143914387

Molecular consequence:

NM_000465.4:c.33G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282543.2:c.33G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282545.2:c.33G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282548.2:c.33G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001282549.2:c.33G>T - missense variant - [Sequence Ontology: SO:0001583]
NR_104212.2:n.147G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_104215.2:n.147G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_104216.2:n.147G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

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
SCV000149542	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely benign (Sep 26, 2020)	germline	clinical testing	Citation Link,
SCV000696772	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (May 3, 2016)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25980754, 23056176, 26787654, 26898890 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000806127	PreventionGenetics, part of Exact Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Jan 30, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000887591	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Benign (Jun 22, 2022)	unknown	clinical testing	PubMed (8) [See all records that cite these PMIDs] 26315354, 27443514, 34906988, 25980754, 27328445, 26898890, 27978560, 26467025
SCV001553371	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Likely benign	unknown	clinical testing
SCV001799931	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus	no assertion criteria provided	Likely benign	germline	clinical testing
SCV001807584	Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus	no assertion criteria provided	Likely benign	germline	clinical testing
SCV001967372	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely benign	germline	clinical testing
SCV002009140	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Nov 3, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004151320	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely benign (Mar 1, 2024)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	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
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification of functional SNPs in BARD1 gene and in silico analysis of damaging SNPs: based on data procured from dbSNP database.

Alshatwi AA, Hasan TN, Syed NA, Shafi G, Grace BL.

PLoS One. 2012;7(10):e43939. doi: 10.1371/journal.pone.0043939. Epub 2012 Oct 9.

PubMed [citation]

PMID:: 23056176
PMCID:: PMC3467277

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

See all PubMed Citations (11)

Details of each submission

From GeneDx, SCV000149542.9

#	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, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27978560, 28135145, 25980754, 23056176, 26898890, 26787654, 27328445, 26979391, 27621404, 27498913, 26315354, 28528518, 28873162, 27443514)

#	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, SCV000696772.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: The c.33G>T (p.Gln11His) in BARD1 gene is a missense variant involves a non-conserved nucleotide and 5/5 in silico tools predict benign outcome. The variant is present in the control population dataset of ExAC at a frequency of 0.3% (115/37748 chrs tested), being most prevalent in Europeans (12/1030chrs tested), which exceeds the maximal expected allele frequency for a non-common pathogenic BARD1 variant (0.0002188). However, ExAC include a warning note that this variant is only covered in 18874 individuals (adjusted allele number = 37748). This means that the site is covered in fewer than 80% of the individuals in ExAC, which may indicate a low-quality site.The variant has been reported in affected individuals without strong evidence for causality. The variant of interest has been reported as Likely Benign/Benign by reputable databases/clinical laboratories. Taken all together, the variant was classified as 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 PreventionGenetics, part of Exact Sciences, SCV000806127.1

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000887591.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

#	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 Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001553371.1

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

Description

The BARD1 p.Gln11His variant was identified in 4 of 3420 proband chromosomes (frequency: 0.001) from individuals or families with CRC and Lynch associated cancer (Pearlman 2017, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs143914387) as â€šÃ„Ãºwith other alleleâ€šÃ„Ã¹, and in the ClinVar and Clinvitae databases (as benign by Invitae and likely benign by GeneDx, Ambry Genetics, Illumina Clinical Services, Counsyl, and Quest Diagnostics Nichols Institute San Juan Capistrano). The variant was also identified in the Zhejiang Colon Cancer database 1x but no clinical information was provided. The variant was not identified in the Cosmic and MutDB databases. The variant was identified in the 1000 Genomes Project in 2 of 5000 chromosomes (frequency: 0.0004) and in the NHLBI GO Exome Sequencing Project in 19 of 7906 European American alleles (freq. 0.002). In addition, the variant was identified in control databases in 344 of 213748 chromosomes (1 homozygous) at a frequency of 0.002, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 3 of 18190 chromosomes (freq: 0.0002), Other in 16 of 5410 chromosomes (freq: 0.003), Latino in 72 of 30394 chromosomes (freq: 0.002), European Non-Finnish in 178 of 92742 chromosomes (freq: 0.002), Ashkenazi Jewish in 7 of 8982 chromosomes (freq: 0.0008), European Finnish in 57 of 16012 chromosomes (freq: 0.004), and South Asian in 11 of 26824 chromosomes (freq: 0.0004) while the variant was not observed in the East Asian population. The p.Gln11His residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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

From Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus, SCV001799931.1

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

From Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus, SCV001807584.1

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

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001967372.1

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

From Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden, SCV002009140.3

#	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	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV004151320.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	not provided

Description

BARD1: BS1

#	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		2	not provided	not provided	not provided

Last Updated: Oct 20, 2024

Relating variation to medicine