NM_000465.4(BARD1):c.776A>G (p.Asp259Gly) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 5, 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:: RCV000115643.17

Allele description [Variation Report for NM_000465.4(BARD1):c.776A>G (p.Asp259Gly)]

NM_000465.4(BARD1):c.776A>G (p.Asp259Gly)

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.776A>G (p.Asp259Gly)

Other names:

p.D259G:GAC>GGC

HGVS:

NC_000002.12:g.214781098T>C
NG_012047.3:g.33614A>G
NM_000465.4:c.776A>GMANE SELECT
NM_001282543.2:c.719A>G
NM_001282545.2:c.215+15963A>G
NM_001282548.2:c.158+28314A>G
NM_001282549.2:c.364+11199A>G
NP_000456.2:p.Asp259Gly
NP_001269472.1:p.Asp240Gly
LRG_297t1:c.776A>G
LRG_297:g.33614A>G
LRG_297p1:p.Asp259Gly
NC_000002.11:g.215645822T>C
NG_012047.2:g.33607A>G
NM_000465.2:c.776A>G
NM_000465.3:c.776A>G
NR_104212.2:n.741A>G
NR_104215.2:n.684A>G
p.D259G

Protein change:

D240G

Links:

dbSNP: rs587780036

NCBI 1000 Genomes Browser:

rs587780036

Molecular consequence:

NM_001282545.2:c.215+15963A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001282548.2:c.158+28314A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001282549.2:c.364+11199A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000465.4:c.776A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001282543.2:c.719A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_104212.2:n.741A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_104215.2:n.684A>G - 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
SCV000214886	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Mar 3, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25186627, 25318351, 32832836, 32866190 Citation Link,
SCV000682816	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 5, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 25186627, 25318351, 32832836, 32866190, 33471991, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000214886

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Mar 3, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV000682816

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 5, 2024)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel.

Tung N, Battelli C, Allen B, Kaldate R, Bhatnagar S, Bowles K, Timms K, Garber JE, Herold C, Ellisen L, Krejdovsky J, DeLeonardis K, Sedgwick K, Soltis K, Roa B, Wenstrup RJ, Hartman AR.

Cancer. 2015 Jan 1;121(1):25-33. doi: 10.1002/cncr.29010. Epub 2014 Sep 3.

PubMed [citation]

PMID:: 25186627

Use of panel tests in place of single gene tests in the cancer genetics clinic.

Yorczyk A, Robinson LS, Ross TS.

Clin Genet. 2015 Sep;88(3):278-82. doi: 10.1111/cge.12488. Epub 2014 Oct 16.

PubMed [citation]

PMID:: 25318351

See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV000214886.8

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

Description

The p.D259G variant (also known as c.776A>G), located in coding exon 4 of the BARD1 gene, results from an A to G substitution at nucleotide position 776. The aspartic acid at codon 259 is replaced by glycine, an amino acid with similar properties. This variant was observed in an individual with early onset-breast cancer amongst a cohort of 1781 non-Ashkenazi Jewish individuals undergoing BRCA1/2 gene testing based on a personal history of breast cancer (Tung N et al. Cancer, 2015 Jan;121:25-33). This variant was detected in a cohort 97 (35 African American and 62 European American) seemingly unrelated breast cancer cases (Bishop MR et al. PLoS One, 2020 Aug;15:e0238295). This variant was also identified in a cohort of 3579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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 Color Diagnostics, LLC DBA Color Health, SCV000682816.5

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

Description

This missense variant replaces aspartic acid with glycine at codon 259 of the BARD1 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 25186627, 32866190), an individual affected with prostate cancer (PMID: 32832836), and in individual(s) who underwent hereditary cancer genetic testing (PMID: 25318351). In an international breast cancer case-control meta-analysis, this variant was detected in 2/60466 cases and 1/53461 unaffected controls (PMID: 33471991). This variant has been identified in 2/257946 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is 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

Last Updated: Sep 29, 2024

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