This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
ClinVar Genomic variation as it relates to human health
NM_000135.4(FANCA):c.2658G>C (p.Glu886Asp)
Germline
Classification
Help
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.
(11)
Help
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.
Conflicting classifications of pathogenicity
Uncertain significance(9); Likely benign(1)
Uncertain significance(9); Likely benign(1)
11
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000135.4(FANCA):c.2658G>C (p.Glu886Asp)
Variation ID: 456101 Accession: VCV000456101.28
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16q24.3 16: 89765010 (GRCh38) [ NCBI UCSC ] 16: 89831418 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Oct 10, 2018 Feb 20, 2024 Feb 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000135.4:c.2658G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000126.2:p.Glu886Asp missense NM_000135.3:c.2658G>C NM_001286167.3:c.2658G>C NP_001273096.1:p.Glu886Asp missense NC_000016.10:g.89765010C>G NC_000016.9:g.89831418C>G NG_011706.1:g.56648G>C LRG_495:g.56648G>C LRG_495t1:c.2658G>C - Protein change
- E886D
- Other names
- -
- Canonical SPDI
- NC_000016.10:89765009:C:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00021
The Genome Aggregation Database (gnomAD), exomes 0.00023
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00038
The Genome Aggregation Database (gnomAD) 0.00055
Trans-Omics for Precision Medicine (TOPMed) 0.00082
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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. |
|||
| FANCA | - | - |
GRCh38 GRCh37 |
4166 | 5324 | |
| LOC130059837 | - | - | - | GRCh38 | - | 137 |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Feb 1, 2024 | RCV000542670.18 | |
| Uncertain significance (6) |
criteria provided, multiple submitters, no conflicts
|
Nov 13, 2023 | RCV001120360.11 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Jun 23, 2023 | RCV001562680.5 | |
|
FANCA-related disorder
|
Uncertain significance (1) |
criteria provided, single submitter
|
Aug 16, 2023 | RCV003409764.4 |
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
Help
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Jan 12, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Fanconi anemia complementation group A
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001278841.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
|
|
|
Uncertain significance
(Feb 05, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Fanconi anemia complementation group A
Affected status: yes
Allele origin:
paternal
|
Baylor Genetics
Accession: SCV001525761.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
|
|
|
Uncertain significance
(Aug 21, 2021)
|
criteria provided, single submitter
Method: curation
|
Fanconi anemia
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002534963.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The FANCA c.2658G>C (p.E886D) variant has been reported in individuals with breast cancer, prostate cancer, ovarian cancer, and Li-Fraumeni syndrome as well as in controls … (more)
The FANCA c.2658G>C (p.E886D) variant has been reported in individuals with breast cancer, prostate cancer, ovarian cancer, and Li-Fraumeni syndrome as well as in controls (PMID: 34130653, 32268276, 30268473, 32546565). In the Li-Fraumeni syndrome and prostate cancer patients, additional pathogenic variant were also observed which are likely to explain the disease (PMID: 34130653, 32268276, 30268473, 32546565). This variant was observed in 60/129188 chromosomes of the Non-Finnish European subpopulation 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 456101). Functional studies have not been performed, and in silico predictions of the variant's effect on protein function are inconclusive. There is no indication that this variant causes disease, but the evidence is insufficient currently to prove that conclusively. Thus, the clinical significance of this variant is currently uncertain. (less)
|
|
|
|
Uncertain significance
(Feb 25, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001785484.3
First in ClinVar: Aug 14, 2021 Last updated: Mar 04, 2023 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
|
|
|
Uncertain significance
(Dec 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Fanconi anemia complementation group A
Affected status: unknown
Allele origin:
maternal
|
Institute of Human Genetics, Cologne University
Accession: SCV003936906.1
First in ClinVar: Jul 08, 2023 Last updated: Jul 08, 2023 |
|
|
|
Uncertain significance
(Aug 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
FANCA-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004113219.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The FANCA c.2658G>C variant is predicted to result in the amino acid substitution p.Glu886Asp. This variant has been detected in patients with breast cancer and … (more)
The FANCA c.2658G>C variant is predicted to result in the amino acid substitution p.Glu886Asp. This variant has been detected in patients with breast cancer and epithelial ovarian cancer, as well as in control individuals in one study (Bakos et al. 2021. PubMed ID: 34130653, Table S6, Song et al. 2020. PubMed ID: 32546565). This variant is reported in 0.046% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-89831418-C-G) and is interpreted as uncertain and likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/456101/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
|
|
|
Uncertain significance
(Nov 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Fanconi anemia complementation group A
Affected status: unknown
Allele origin:
germline
|
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV002012432.4
First in ClinVar: Nov 11, 2021 Last updated: Dec 02, 2023 |
Comment:
The FANCA c.2658G>C (p.Glu886Asp) missense change has a maximum subpopulation frequency of 0.046% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign … (more)
The FANCA c.2658G>C (p.Glu886Asp) missense change has a maximum subpopulation frequency of 0.046% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. The variant has been reported as heterozygous in one individual with breast cancer (PMID: 34130653). To our knowledge, this variant has not been reported in individuals with Fanconi anemia. 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)
|
|
|
Uncertain significance
(Jun 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004221976.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
In the published literature, this variant has been reported in individuals with ovarian cancer (PMID: 32546565 (2021)), breast cancer (PMID: 34130653 (2021)), and Li-Fraumeni syndrome … (more)
In the published literature, this variant has been reported in individuals with ovarian cancer (PMID: 32546565 (2021)), breast cancer (PMID: 34130653 (2021)), and Li-Fraumeni syndrome (LFS) (PMID: 30268473 (2018)). This variant was also reported in healthy individuals (PMID: 32546565 (2021)). The frequency of this variant in the general population, 0.00095 (11/11610 chromosomes in Southern European subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
|
|
|
Uncertain significance
(Sep 11, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Fanconi anemia complementation group A
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003832352.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Likely benign
(Feb 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Fanconi anemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000626171.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
|
|
|
Uncertain significance
(Dec 24, 2019)
|
no assertion criteria provided
Method: clinical testing
|
Fanconi anemia, group A
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001458826.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
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Comment:
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Comment:
The FANCA c.2658G>C variant is predicted to result in the amino acid substitution p.Glu886Asp. This variant has been detected in patients with breast cancer and epithelial ovarian cancer, as well as in control individuals in one study (Bakos et al. 2021. PubMed ID: 34130653, Table S6, Song et al. 2020. PubMed ID: 32546565). This variant is reported in 0.046% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-89831418-C-G) and is interpreted as uncertain and likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/456101/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Comment:
The FANCA c.2658G>C (p.Glu886Asp) missense change has a maximum subpopulation frequency of 0.046% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. The variant has been reported as heterozygous in one individual with breast cancer (PMID: 34130653). To our knowledge, this variant has not been reported in individuals with Fanconi anemia. 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.
Comment:
In the published literature, this variant has been reported in individuals with ovarian cancer (PMID: 32546565 (2021)), breast cancer (PMID: 34130653 (2021)), and Li-Fraumeni syndrome (LFS) (PMID: 30268473 (2018)). This variant was also reported in healthy individuals (PMID: 32546565 (2021)). The frequency of this variant in the general population, 0.00095 (11/11610 chromosomes in Southern European subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
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. |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Comment:
The FANCA c.2658G>C variant is predicted to result in the amino acid substitution p.Glu886Asp. This variant has been detected in patients with breast cancer and epithelial ovarian cancer, as well as in control individuals in one study (Bakos et al. 2021. PubMed ID: 34130653, Table S6, Song et al. 2020. PubMed ID: 32546565). This variant is reported in 0.046% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-89831418-C-G) and is interpreted as uncertain and likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/456101/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Comment:
The FANCA c.2658G>C (p.Glu886Asp) missense change has a maximum subpopulation frequency of 0.046% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. The variant has been reported as heterozygous in one individual with breast cancer (PMID: 34130653). To our knowledge, this variant has not been reported in individuals with Fanconi anemia. 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.
Comment:
In the published literature, this variant has been reported in individuals with ovarian cancer (PMID: 32546565 (2021)), breast cancer (PMID: 34130653 (2021)), and Li-Fraumeni syndrome (LFS) (PMID: 30268473 (2018)). This variant was also reported in healthy individuals (PMID: 32546565 (2021)). The frequency of this variant in the general population, 0.00095 (11/11610 chromosomes in Southern European subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Co-occurrence of thyroid and breast cancer is associated with an increased oncogenic SNP burden. | Bakos B | BMC cancer | 2021 | PMID: 34130653 |
| Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer. | Song H | Journal of medical genetics | 2021 | PMID: 32546565 |
| Clinical and genomic insights into circulating tumor DNA-based alterations across the spectrum of metastatic hormone-sensitive and castrate-resistant prostate cancer. | Kohli M | EBioMedicine | 2020 | PMID: 32268276 |
| Probable hereditary familial overlap syndrome with multiple synchronous lung tumors. | Cardona AF | Lung cancer (Amsterdam, Netherlands) | 2018 | PMID: 30268473 |
Text-mined citations for rs139002130 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.