ClinVar Genomic variation as it relates to human health
NM_000136.3(FANCC):c.1493C>T (p.Ala498Val)
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.1493C>T (p.Ala498Val)
Variation ID: 182488 Accession: VCV000182488.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q22.32 9: 95107106 (GRCh38) [ NCBI UCSC ] 9: 97869388 (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 1, 2024 Dec 29, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000136.3:c.1493C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000127.2:p.Ala498Val missense NM_001243743.2:c.1493C>T NP_001230672.1:p.Ala498Val missense NC_000009.12:g.95107106G>A NC_000009.11:g.97869388G>A NG_011707.1:g.215604C>T LRG_497:g.215604C>T LRG_497t1:c.1493C>T - Protein change
- A498V
- Other names
- p.A498V:GCT>GTT
- Canonical SPDI
- NC_000009.12:95107105:G:A
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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.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
The Genome Aggregation Database (gnomAD) 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00004
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
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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 |
24 | 1348 | |
FANCC | - | - |
GRCh38 GRCh37 |
633 | 1961 |
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 (1) |
criteria provided, single submitter
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Apr 27, 2023 | RCV000160489.9 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Dec 29, 2023 | RCV000204351.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 14, 2023 | RCV001011857.4 | |
Uncertain significance (5) |
criteria provided, multiple submitters, no conflicts
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Sep 28, 2022 | RCV001167958.11 |
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
(Nov 12, 2021)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia complementation group C
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002782107.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Sep 28, 2022)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia complementation group C
Affected status: unknown
Allele origin:
germline
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St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV002526040.2
First in ClinVar: Jun 16, 2022 Last updated: Oct 22, 2022 |
Comment:
The FANCC c.1493C>T (p.Ala498Val) missense change has a maximum subpopulation frequency of 0.0021% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign … (more)
The FANCC c.1493C>T (p.Ala498Val) missense change has a maximum subpopulation frequency of 0.0021% 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. This variant has been reported in individuals with breast cancer (PMID: 23028338) and ovarian cancer (PMID: 32546565). 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)
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Uncertain significance
(Apr 27, 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: SCV000211054.18
First in ClinVar: Feb 24, 2015 Last updated: May 06, 2023 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer or ovarian cancer (Thompson et al., … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer or ovarian cancer (Thompson et al., 2012; Song et al., 2021); This variant is associated with the following publications: (PMID: 32546565, 23028338) (less)
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Uncertain significance
(Dec 29, 2023)
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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: SCV000260179.7
First in ClinVar: Jan 31, 2016 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 498 of the FANCC protein (p.Ala498Val). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 498 of the FANCC protein (p.Ala498Val). This variant is present in population databases (rs730881725, gnomAD 0.005%). This missense change has been observed in individual(s) with family history of breast cancer (PMID: 23028338). ClinVar contains an entry for this variant (Variation ID: 182488). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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
(Dec 14, 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: SCV001172231.4
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The p.A498V variant (also known as c.1493C>T), located in coding exon 13 of the FANCC gene, results from a C to T substitution at nucleotide … (more)
The p.A498V variant (also known as c.1493C>T), located in coding exon 13 of the FANCC gene, results from a C to T substitution at nucleotide position 1493. The alanine at codon 498 is replaced by valine, an amino acid with similar properties. This alteration was detected in a cohort of 438 breast cancer families (Thompson ER et al. PLoS Genet, 2012 Sep;8:e1002894). This amino acid position is not 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
(May 15, 2017)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia complementation group C
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001330509.1
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 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: SCV002535093.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The FANCC c.1493C>T (p.A498V) variant has been reported in at least three individuals with breast cancer and at least one individual with ovarian cancer (PMID: … (more)
The FANCC c.1493C>T (p.A498V) variant has been reported in at least three individuals with breast cancer and at least one individual with ovarian cancer (PMID: 33471991, 32546565, 23028338). However, this variant has also been identified in at least two unaffected controls (PMID: 33471991). It was observed in 6/129114 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: 182488). In silico tools suggest the impact of the variant on protein function is benign, 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
(-)
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no assertion criteria provided
Method: clinical testing
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Fanconi anemia complementation group C
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: SCV001549863.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The FANCC p.Ala498Val variant was identified in 1 of 2882 proband chromosomes (frequency: 0.0004) from individuals or families with breast cancer and was not identified … (more)
The FANCC p.Ala498Val variant was identified in 1 of 2882 proband chromosomes (frequency: 0.0004) from individuals or families with breast cancer and was not identified in 928 control chromosomes from healthy individuals (Thompson 2012). The variant was also identified in dbSNP (ID: rs730881725) as "With Uncertain significance allele" and ClinVar (classified as uncertain significance by Invitae and GeneDx). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 6 of 277174 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 6 of 126674 chromosomes (freq: 0.00005), while it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Ala498 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, 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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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: SCV001457636.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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 |
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 |
Exome sequencing identifies rare deleterious mutations in DNA repair genes FANCC and BLM as potential breast cancer susceptibility alleles. | Thompson ER | PLoS genetics | 2012 | PMID: 23028338 |
Text-mined citations for rs730881725 ...
HelpRecord last updated May 08, 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.