NM_000465.4(BARD1):c.1977A>G (p.Arg659=) AND Familial cancer of breast

Germline classification:: Conflicting interpretations of pathogenicity (7 submissions)
Last evaluated:: Feb 1, 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:: RCV000200663.39

Allele description [Variation Report for NM_000465.4(BARD1):c.1977A>G (p.Arg659=)]

NM_000465.4(BARD1):c.1977A>G (p.Arg659=)

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.1977A>G (p.Arg659=)

Other names:

p.R659R:AGA>AGG

HGVS:

NC_000002.12:g.214730435T>C
NG_012047.3:g.84277A>G
NM_000465.4:c.1977A>GMANE SELECT
NM_001282543.2:c.1920A>G
NM_001282545.2:c.624A>G
NM_001282548.2:c.567A>G
NM_001282549.2:c.438A>G
NP_000456.2:p.Arg659=
NP_001269472.1:p.Arg640=
NP_001269474.1:p.Arg208=
NP_001269477.1:p.Arg189=
NP_001269478.1:p.Arg146=
LRG_297t1:c.1977A>G
LRG_297:g.84277A>G
LRG_297p1:p.Arg659=
NC_000002.11:g.215595159T>C
NG_012047.2:g.84270A>G
NM_000465.2:c.1977A>G
NM_000465.3:c.1977A>G
NR_104212.2:n.1942A>G
NR_104215.2:n.1885A>G
NR_104216.2:n.1141A>G
p.Arg659Arg
p.R659R

Links:

dbSNP: rs147215925

NCBI 1000 Genomes Browser:

rs147215925

Molecular consequence:

NR_104212.2:n.1942A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_104215.2:n.1885A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_104216.2:n.1141A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_000465.4:c.1977A>G - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001282543.2:c.1920A>G - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001282545.2:c.624A>G - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001282548.2:c.567A>G - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001282549.2:c.438A>G - synonymous variant - [Sequence Ontology: SO:0001819]

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
SCV000252705	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Benign (Feb 1, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000611875	University of Washington Department of Laboratory Medicine, University of Washington	criteria provided, single submitter (Tsai GJ et al. (Genet Med 2018))	Likely benign (Mar 28, 2018)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV000785727	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Likely benign (Nov 9, 2017)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26787654, 25994375, 21344236 Counsyl_Autosomal_Dominant_Disease_Classification_criteria_(2015)_v1.pdf, Citation Link,
SCV000837946	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Likely benign (Jul 2, 2018)	unknown	clinical testing	Citation Link,
SCV000885059	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Likely benign (Oct 19, 2023)	germline	clinical testing	Citation Link,
SCV001298994	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 27, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV004019251	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Benign (Feb 24, 2023)	unknown	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	1	not provided	not provided	yes	research
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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Outcomes of 92 patient-driven family studies for reclassification of variants of uncertain significance.

Tsai GJ, Rañola JMO, Smith C, Garrett LT, Bergquist T, Casadei S, Bowen DJ, Shirts BH.

Genet Med. 2019 Jun;21(6):1435-1442. doi: 10.1038/s41436-018-0335-7. Epub 2018 Oct 30.

PubMed [citation]

PMID:: 30374176

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000252705.11

#	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 University of Washington Department of Laboratory Medicine, University of Washington, SCV000611875.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	yes	research	PubMed (1)

Description

The BARD1 variant designated as NM_000465.3:c.1977A>G (p.Arg659=) is classified as likely benign. The variant is present in approximately 1 in every 170 individuals with European ancestry (exac.broadinstitute.org), which is more common than cancer risk variants. In one observed family, the allele did not travel with breast cancer in the family, providing additional evidence that the BARD1 p.Arg659= is benign. This variant has been classified as likely benign by other laboratories (ClinVar Variation ID: 127727). Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives a <1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter BARD1 function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This reclassification analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	1	not provided

From Counsyl, SCV000785727.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

#	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, SCV000837946.2

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000885059.6

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

From Illumina Laboratory Services, Illumina, SCV001298994.1

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown 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., SCV004019251.1

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

Description

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.

#	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: Oct 20, 2024

Relating variation to medicine