ClinVar Genomic variation as it relates to human health
NM_000136.3(FANCC):c.1249G>A (p.Glu417Lys)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000136.3(FANCC):c.1249G>A (p.Glu417Lys)
Variation ID: 182485 Accession: VCV000182485.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q22.32 9: 95111543 (GRCh38) [ NCBI UCSC ] 9: 97873825 (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 Apr 15, 2023 Apr 4, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000136.3:c.1249G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000127.2:p.Glu417Lys missense NM_001243743.2:c.1249G>A NP_001230672.1:p.Glu417Lys missense NM_001243744.2:c.1249G>A NP_001230673.1:p.Glu417Lys missense NC_000009.12:g.95111543C>T NC_000009.11:g.97873825C>T NG_011707.1:g.211167G>A LRG_497:g.211167G>A LRG_497t1:c.1249G>A - Protein change
- E417K
- Other names
- p.E417K:GAA>AAA
- Canonical SPDI
- NC_000009.12:95111542:C:T
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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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00006
Exome Aggregation Consortium (ExAC) 0.00007
The Genome Aggregation Database (gnomAD) 0.00010
Trans-Omics for Precision Medicine (TOPMed) 0.00011
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00031
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 | ||
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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
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. |
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AOPEP | - | - |
GRCh38 GRCh37 |
13 | 1300 | |
FANCC | - | - |
GRCh38 GRCh37 |
610 | 1902 |
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. |
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Uncertain significance (2) |
criteria provided, single submitter
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Apr 4, 2023 | RCV000160486.9 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Oct 28, 2022 | RCV000477242.7 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 10, 2023 | RCV000570128.4 | |
Uncertain significance (2) |
criteria provided, single submitter
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Feb 9, 2021 | RCV001273988.3 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV001358089.2 |
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. |
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Uncertain significance
(Oct 28, 2022)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000549948.7
First in ClinVar: Apr 17, 2017 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 417 of the FANCC protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 417 of the FANCC protein (p.Glu417Lys). This variant is present in population databases (rs140687953, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 182485). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FANCC 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
(Jan 10, 2023)
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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: SCV000673337.5
First in ClinVar: Jan 01, 2018 Last updated: Apr 15, 2023 |
Comment:
The p.E417K variant (also known as c.1249G>A), located in coding exon 12 of the FANCC gene, results from a G to A substitution at nucleotide … (more)
The p.E417K variant (also known as c.1249G>A), located in coding exon 12 of the FANCC gene, results from a G to A substitution at nucleotide position 1249. The glutamic acid at codon 417 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in several breast cancer patients as well as controls (Seal S et al. Cancer Res. 2003 Dec;63:8596-9; Lerner-Ellis J et al. J Cancer Res Clin Oncol. 2021 Mar;147:871-879; Dorling et al. N Engl J Med. 2021 Feb;384:428-439; Song H et al. J Med Genet. 2021 May;58:305-313). 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
(Apr 04, 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: SCV000211051.16
First in ClinVar: Feb 24, 2015 Last updated: Apr 15, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer and in unaffected controls … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer and in unaffected controls (Dorling et al., 2021); Absent in individuals with ovarian cancer but observed in unaffected controls (Song et al., 2020); This variant is associated with the following publications: (PMID: 14695169, 33471991, Gordon2000[Book], 32546565) (less)
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Uncertain significance
(Feb 09, 2021)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia complementation group C
Affected status: yes
Allele origin:
unknown
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Baylor Genetics
Study: CSER-TexasKidsCanSeq
Accession: SCV002030202.1 First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021 |
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
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Uncertain significance
(Jun 09, 2021)
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criteria provided, single submitter
Method: curation
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Fanconi anemia
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002535084.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Uncertain significance
(Feb 28, 2020)
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no assertion criteria provided
Method: curation
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not provided
Affected status: yes
Allele origin:
germline
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Leiden Open Variation Database
Accession: SCV001365334.1
First in ClinVar: Jun 29, 2020 Last updated: Jun 29, 2020 |
Comment:
Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.
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Uncertain significance
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Fanconi anemia, group C
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001457649.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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: SCV001553738.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The FANCC p.Glu417Lys variant was identified in 1 of 172 proband chromosomes (frequency: 0.006) from individuals or families with breast cancer and was present in … (more)
The FANCC p.Glu417Lys variant was identified in 1 of 172 proband chromosomes (frequency: 0.006) from individuals or families with breast cancer and was present in 1 of 600 control chromosomes (frequency: 0.002) from healthy individuals (Seal 2003). The variant was also identified in dbSNP (ID: rs140687953) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by GeneDx, Invitae and Ambry Genetics), and LOVD 3.0 (not classified). The variant was identified in control databases in 18 of 277164 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 5 of 24026 chromosomes (freq: 0.0002), Latino in 2 of 34418 chromosomes (freq: 0.00006), and European Non-Finnish in 11 of 126668 chromosomes (freq: 0.00009), while the variant was not observed in the Other, Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. The p.Glu417 residue is conserved in mammals but not in more distantly related organisms; however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; 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) 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)
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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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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 |
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 |
LOVD v.2.0: the next generation in gene variant databases. | Fokkema IF | Human mutation | 2011 | PMID: 21520333 |
Evaluation of Fanconi Anemia genes in familial breast cancer predisposition. | Seal S | Cancer research | 2003 | PMID: 14695169 |
Text-mined citations for rs140687953 ...
HelpRecord last updated Dec 25, 2023
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.