rs774170058
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000136.3(FANCC):βc.455_456insAβ(p.Asn152LysfsTer9) variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.0000082 in 1,585,636 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 32)
Exomes π: 0.0000084 ( 0 hom. )
Consequence
FANCC
NM_000136.3 frameshift, splice_region
NM_000136.3 frameshift, splice_region
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.61
Genes affected
FANCC (HGNC:3584): (FA complementation group C) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group C. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
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Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 9-95172037-A-AT is Pathogenic according to our data. Variant chr9-95172037-A-AT is described in ClinVar as [Pathogenic]. Clinvar id is 409657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FANCC | NM_000136.3 | c.455_456insA | p.Asn152LysfsTer9 | frameshift_variant, splice_region_variant | 5/15 | ENST00000289081.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FANCC | ENST00000289081.8 | c.455_456insA | p.Asn152LysfsTer9 | frameshift_variant, splice_region_variant | 5/15 | 1 | NM_000136.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152238Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250668Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135612
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GnomAD4 exome AF: 0.00000837 AC: 12AN: 1433398Hom.: 0 Cov.: 27 AF XY: 0.00000839 AC XY: 6AN XY: 715040
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:10Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Fanconi anemia complementation group C Pathogenic:5Other:1
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jun 03, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 04, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 05, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 10, 2020 | Variant summary: FANCC c.455dupA (p.Asn152LysfsX9) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.6e-05 in 250668 control chromosomes. c.455dupA has been reported in the literature in at-least one individual affected with Fanconi Anemia and has been subsequently cited by others in settings of tumor testing (example, Yates_2006, Ameziane_2008, Pilonetto_2017, Kato_2017, Cheng_2015, Waszak_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=4)/likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | curation | Leiden Open Variation Database | Feb 28, 2020 | Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Johan de Winter. - |
not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Pathogenic and reported on 08-03-2017 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. - |
Fanconi anemia Pathogenic:2
Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 18, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change creates a premature translational stop signal (p.Asn152Lysfs*9) in the FANCC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FANCC are known to be pathogenic (PMID: 17924555). This variant is present in population databases (rs774170058, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with Fanconi anemia (PMID: 16429406). ClinVar contains an entry for this variant (Variation ID: 409657). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 20, 2023 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Observed in individuals with colorectal, medulloblastoma, melanoma, and stomach cancer (PMID: 26689913, 29625052, 29753700, 33050356); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29038235, 25801821, 28717661, 29753700, 17924555, 26689913, 29922827, 29625052, 33050356, 36451132, 16429406) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2023 | FANCC: PVS1, PM2 - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 20, 2022 | The c.455dupA pathogenic mutation, located in coding exon 4 of the FANCC gene, results from a duplication of A at nucleotide position 455, causing a translational frameshift with a predicted alternate stop codon (p.N152Kfs*9). This mutation (designated as c.455_456dupA) has been reported in the compound heterozygous state with another FANCC mutation in a patient with Fanconi anemia (Yates J et al. Hum. Mutat. 2006 Feb;27:214). It was also observed in an 11-year-old male with medulloblastoma (Waszak SM et al. Lancet Oncol. 2018 06;19:785-798). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at