ClinVar Genomic variation as it relates to human health
NM_000465.4(BARD1):c.659T>C (p.Leu220Ser)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(11); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000465.4(BARD1):c.659T>C (p.Leu220Ser)
Variation ID: 142225 Accession: VCV000142225.59
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q35 2: 214781215 (GRCh38) [ NCBI UCSC ] 2: 215645939 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 19, 2017 May 12, 2024 Jan 30, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000465.4:c.659T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000456.2:p.Leu220Ser missense NM_001282543.2:c.602T>C NP_001269472.1:p.Leu201Ser missense NM_001282545.2:c.215+15846T>C intron variant NM_001282548.2:c.158+28197T>C intron variant NM_001282549.2:c.364+11082T>C intron variant NR_104212.2:n.624T>C non-coding transcript variant NR_104215.2:n.567T>C non-coding transcript variant NC_000002.12:g.214781215A>G NC_000002.11:g.215645939A>G NG_012047.3:g.33497T>C LRG_297:g.33497T>C LRG_297t1:c.659T>C LRG_297p1:p.Leu220Ser - Protein change
- L220S, L201S
- Other names
- p.L220S:TTA>TCA
- Canonical SPDI
- NC_000002.12:214781214:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00010
The Genome Aggregation Database (gnomAD) 0.00013
Trans-Omics for Precision Medicine (TOPMed) 0.00016
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00031
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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BARD1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3939 | 3993 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jun 1, 2022 | RCV000131224.15 | |
Uncertain significance (4) |
criteria provided, multiple submitters, no conflicts
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Jan 30, 2024 | RCV000205881.20 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Jul 20, 2023 | RCV000585398.30 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Aug 15, 2023 | RCV000855575.6 | |
Uncertain significance (2) |
no assertion criteria provided
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- | RCV001357448.4 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Jul 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000209841.18
First in ClinVar: Feb 24, 2015 Last updated: Jul 29, 2023 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with brain cancer, breast cancer and/or ovarian cancer, and … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with brain cancer, breast cancer and/or ovarian cancer, and in unaffected controls in a breast cancer study (Ramus et al., 2015; Zhang et al., 2015; Syeda et al., 2017; Lerner-Ellis et al., 2021; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 28301456, 26315354, 23056176, 21796119, 26580448, Maurer_2022, 32885271, 33471991) (less)
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Uncertain significance
(Oct 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004214958.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Uncertain significance
(Jan 30, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000259944.12
First in ClinVar: Jan 31, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 220 of the BARD1 protein (p.Leu220Ser). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 220 of the BARD1 protein (p.Leu220Ser). This variant is present in population databases (rs138593305, gnomAD 0.02%). This missense change has been observed in individual(s) with breast and/or ovarian cancer and brain tumor (PMID: 26315354, 26580448, 28301456, 36187937). ClinVar contains an entry for this variant (Variation ID: 142225). 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 serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. (less)
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Uncertain significance
(Aug 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV000693039.25
First in ClinVar: Mar 03, 2018 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Likely benign
(Oct 27, 2015)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000902724.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001296631.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
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, … (more)
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. (less)
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Uncertain significance
(Nov 10, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000887600.2
First in ClinVar: Mar 13, 2019 Last updated: Jan 01, 2022 |
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Uncertain significance
(Dec 28, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002529639.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The BARD1 c.659T>C (p.L220S) variant has been reported in heterozygosity in multiple individuals with breast and/or ovarian cancer and glioma (PMID: 26580448, 28301456, 26315354, 33471991), … (more)
The BARD1 c.659T>C (p.L220S) variant has been reported in heterozygosity in multiple individuals with breast and/or ovarian cancer and glioma (PMID: 26580448, 28301456, 26315354, 33471991), but has also been identified in healthy controls (PMID: 33471991, 26315354). It was observed in 22/123262 chromosomes of the Non-Finnish European subpopulation, with no homozygotes, in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID 142225). In silico tools suggest the impact of the variant on protein function is inconclusive, though these predictions have not been confirmed by functional studies. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
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Uncertain significance
(Apr 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696780.4
First in ClinVar: Mar 03, 2018 Last updated: Jun 03, 2023 |
Comment:
Variant summary: BARD1 c.659T>C (p.Leu220Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more)
Variant summary: BARD1 c.659T>C (p.Leu220Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.9e-05 in 239542 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in BARD1 causing Hereditary Breast And Ovarian Cancer Syndrome (7.9e-05 vs 0.00025), allowing no conclusion about variant significance. c.659T>C has been reported in the literature in individuals affected with Breast cancer, Ovarian Cancer or brain tumors (Ramus_2015, Zhang_2015, Dorling_2021, Maurer_2022) and breast cancer unaffected individuals (Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight (other) submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=7) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Aug 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004024865.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
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Uncertain significance
(Nov 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
germline
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St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV004171400.1
First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023 |
Comment:
The BARD1 c.659T>C (p.Leu220Ser) missense change has a maximum non-founder subpopulation frequency of 0.018% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a … (more)
The BARD1 c.659T>C (p.Leu220Ser) missense change has a maximum non-founder subpopulation frequency of 0.018% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but this prediction has not been confirmed by functional studies. This variant has been reported in a large case-control study of breast cancer in 24 of 60466 and 10 of 53461 controls (PMID: 33471991), and in a smaller case-control study of ovarian cancer in 2 of 3236 cases and 1 of 3431 controls (PMID: 26315354). This variant has also been reported in individuals with breast cancer and high-grade glioma (PMID: 28301456, 26580448). This variant is present in three individuals in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). 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. (less)
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Uncertain significance
(Jun 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000186177.8
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.L220S variant (also known as c.659T>C), located in coding exon 4 of the BARD1 gene, results from a T to C substitution at nucleotide … (more)
The p.L220S variant (also known as c.659T>C), located in coding exon 4 of the BARD1 gene, results from a T to C substitution at nucleotide position 659. The leucine at codon 220 is replaced by serine, an amino acid with dissimilar properties. In one study, this alteration was observed in 2/3236 cases with invasive epithelial ovarian cancer and 1/3431 controls (Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov;107). In another study, this variant was identified in a patient with breast and/or ovarian cancer, who had a positive family history and had negative BRCA1/2 genetic testing (Syeda MM et al. Genet. Med. 2017 Sep;19:1071-1077). This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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Malignant tumor of breast
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001552925.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The BARD1 p.Leu220Ser variant was identified in 2 of 6748 proband chromosomes (frequency: 0.0003) from individuals or families with ovarian cancer (Ramus 2015). The variant … (more)
The BARD1 p.Leu220Ser variant was identified in 2 of 6748 proband chromosomes (frequency: 0.0003) from individuals or families with ovarian cancer (Ramus 2015). The variant was also identified in dbSNP (ID: rs138593305 as "With Uncertain significance allele"), ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, Invitae, and two other clinical laboratories), MutDB, and the Zhejiang University Database. The variant was not identified in the Cosmic database. The variant was identified in control databases in 22 of 257210 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 21 of 120654 chromosomes (freq: 0.0002) and Ashkenazi Jewish in 1 of 8898 chromosomes (freq: 0.0001), but not in the African, Other, Latino, East Asian, Finnish, or South Asian populations. The p.Leu220 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. This variant is classified as a variant of uncertain significance. (less)
Number of individuals with the variant: 1
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not provided
(-)
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no classification provided
Method: phenotyping only
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Malignant tumor of breast
Affected status: unknown
Allele origin:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV001749599.1
First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021 |
Comment:
Variant interpreted as Uncertain significance and reported on 11-20-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpreted as Uncertain significance and reported on 11-20-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Myopia (present) , Abnormal oral cavity morphology (present) , Autoimmunity (present) , Recurrent infections (present) , Abnormal intestine morphology (present) , Abnormal muscle physiology (present) … (more)
Myopia (present) , Abnormal oral cavity morphology (present) , Autoimmunity (present) , Recurrent infections (present) , Abnormal intestine morphology (present) , Abnormal muscle physiology (present) , Abnormality of the somatic nervous system (present) , Abnormal curvature of the vertebral column (present) , Hyperthyroidism (present) , Anxiety (present) , Depression (present) , Pregnancy history (present) , Premature birth (present) (less)
Indication for testing: Presymptomatic
Age: 40-49 years
Sex: female
Testing laboratory: Invitae
Date variant was reported to submitter: 2020-11-20
Testing laboratory interpretation: Uncertain significance
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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BRCA1-associated RING domain-1 (BARD1) loss and GBP1 expression enhance sensitivity to DNA damage in Ewing sarcoma. | Maurer LM | Cancer research communications | 2022 | PMID: 36187937 |
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
Multigene panel testing for hereditary breast and ovarian cancer in the province of Ontario. | Lerner-Ellis J | Journal of cancer research and clinical oncology | 2021 | PMID: 32885271 |
Prediction of breast cancer risk based on flow-variant analysis of circulating peripheral blood B cells. | Syeda MM | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28301456 |
Germline Mutations in Predisposition Genes in Pediatric Cancer. | Zhang J | The New England journal of medicine | 2015 | PMID: 26580448 |
Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer. | Ramus SJ | Journal of the National Cancer Institute | 2015 | PMID: 26315354 |
Identification of functional SNPs in BARD1 gene and in silico analysis of damaging SNPs: based on data procured from dbSNP database. | Alshatwi AA | PloS one | 2012 | PMID: 23056176 |
Text-mined citations for rs138593305 ...
HelpRecord last updated May 12, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.