The FANCC NM_000136.3:c.456+4A>T (NP_000127.2:p.?) intronic variant has previously been reported in somatic cancers (COSMIC; COSV56656439, n = 1 time). Experimental evidence: RT-PCR in FA10 showed c.456+4A>T produced alternatively spliced FANCC transcripts, including exon 6 skipping. Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS).
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.FANCC encodes a protein that helps coordinate the repair of damaged DNA, especially damage that can block DNA copying. Inherited FANCC defects cause Fanconi anemia, a disorder involving bone marrow failure, developmental problems, chromosome instability, and increased cancer risk. FANCC functions as a tumor suppressor, and its loss is associated with several cancers, including leukemia, breast, oral, and pancreatic cancers.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met at supporting strength: RT-PCR in FA10 showed c.456+4A>T produced alternatively spliced FANCC transcripts, including exon 6 skipping.
Met: an affected FA10 patient carried c.456+4A>T paternal in trans with a nonexpressed maternal 8.5-kb FANCC deletion.
Met, moderate: SpliceAI max delta 0.895 exceeds the generic PP3 moderate threshold of >=0.5 for intronic or splice-region variants.
No benign criterion marked as applied in the recorded assessment.
VUS: PS3 (supporting), PM3 (moderate), and PP3 (moderate) provide two moderate plus one supporting evidence, below generic ACMG pathogenic thresholds.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 267 / 1,556,608 alleles. Recorded AF 0.000171527. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 0.000269578; MAF= 0.02696%, 76/281922 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00617999; MAF= 0.61800%, 64/10356 alleles, homozygotes = 0); grpmax FAF= 3.429e-05.
Not available in gnomAD-Canada v1.0.
Recorded SpliceAI maximum delta score: 0.895. Refer to the recorded PP3/BP4 rationale for interpretation.
23 Pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has previously been reported in somatic cancers (COSMIC; COSV56656439, n = 1 times).
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 10 not met · 6 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
For the three requested consequence criteria, PVS1, PM4, and BP3 are not applicable because NM_000136.3:c.456+4A>T is an intronic +4 splice variant with no assigned protein-length change, while PVS1 specifically names canonical +/−1 or 2 splice sites and null coding variant classes.
No VCEP covers FANCC in this case; generic ACMG/AMP rules govern.
PS4 remains not_assessed because the indexed candidate papers requiring verification were unavailable and no verified OR/RR with a 95% CI was available.
PP5 and BP6 were restricted to the supplied exact-variant ClinVar expert-panel rule; the audit reports zero expert-panel submissions.
The allelic evidence supports PM3 from parent-derived trans phase in an affected Fanconi anemia patient; BP2 is not met because no cis observation or dominant-disorder trans observation is documented.
The variant is intronic/splice-region, so PP3 and BP4 were evaluated only through SpliceAI; BP7 is outside scope because the variant is not synonymous.
SpliceAI max delta 0.895 meets PP3 moderate but not BP4, and the prediction was not double-counted across criteria.
No criteria match.
PS3 is met at supporting strength. Chandrasekharappa et al. directly studied FANCC c.456+4A>T in patient FA10 using RT-PCR/RNA analysis and reported that the paternal variant produced alternatively spliced FANCC transcripts, including transcripts skipping the entire exon 6 or 39 bases of exon 6. This is variant-specific functional evidence of abnormal splicing and supports a damaging effect on FANCC. The study involved one patient with a second FANCC allele carrying an 8.5-kb deletion, did not report a protein consequence, and the available record does not establish reproducibility in a validated clinical diagnostic assay; therefore, the evidence is not calibrated above supporting strength.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
PM3 is met for the autosomal-recessive FANCC-associated Fanconi anemia context. Chandrasekharappa et al. report an affected patient (FA10) carrying NM_000136.3:c.456+4A>T as the paternal FANCC allele in trans with a maternal 8.5-kb FANCC deletion removing noncoding exon 1 and 5 kb upstream; the deletion allele was not expressed. This is parent-based phase evidence for the evaluated variant opposite a loss-of-function FANCC allele in an affected individual, satisfying the generic PM3 definition. No VCEP-specific strength framework is available; the criterion is retained at the original ACMG/AMP moderate code strength.
For recessive disorders, detected in trans with a pathogenic variant...This requires testing of parents (or offspring) to determine phase.
Scope settled first: NM_000136.3:c.456+4A>T is an intronic/splice-region variant, so the generic rule requires the SpliceAI path only; REVEL is not applicable and is not used. SpliceAI reports DS_AG 0.000, DS_AL 0.375, DS_DG 0.481, and DS_DL 0.895, with max delta 0.895. This meets the supplied generic SpliceAI PP3 moderate threshold of >=0.5, calibrated by Jaganathan et al. 2019 (PMID:30661751). The same SpliceAI result is not double-counted for BP4 or BP7.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
PS2 is not met. PMID:23613520 reports the exact FANCC c.456+4A>T variant in affected patient FA10 as the paternal mutation, paired with a maternal FANCC deletion. This is documented paternal inheritance, not a de novo occurrence with confirmed maternity and paternity. No evidence establishes a de novo event in another proband.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
PM2 is not met under the supplied generic threshold. The case-specific PM2 supporting cutoff is <=0.0001. The variant is present in both default all-comers population datasets at gnomAD v2.1 AF 0.000269578 (76/281,922) and gnomAD v4.1 AF 0.000171527 (267/1,556,608), each above 0.0001. Although the filtering grpmax FAF values are lower (3.429e-05 in v2.1 and 2.169e-05 in v4.1), the supplied PM2 cutoff is applied to the observed all-comers allele frequency; the variant is therefore not absent or sufficiently rare for PM2 under these generic rules.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
PM6 is not met. PMID:23613520 identifies the exact FANCC c.456+4A>T variant in affected patient FA10 as a paternal mutation, with a maternal deletion as the second allele. The available case therefore documents inheritance from a parent rather than an assumed de novo event.
Assumed de novo, but without confirmation of paternity and maternity.
ClinVar contains an exact-variant Pathogenic classification, but the submission audit reports zero expert-panel submissions; the available assertions are ordinary laboratory or non-expert records. Under the supplied generic PP5 rule, an exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic classification is required. The papers PMID:10666230 and PMID:8128956 report the variant in affected Fanconi anemia patients, but literature reports and non-expert ClinVar assertions do not satisfy the required expert-panel trigger.
Generic rules for PP5/BP6: apply them only for an exact-variant ClinVar expert-panel classification: Pathogenic/Likely pathogenic supports PP5; Benign/Likely benign supports BP6.
BA1 is not met. The supplied generic stand-alone threshold is >=0.05, and the required filtering grpmax FAF is 2.169e-05 in gnomAD v4.1, far below 0.05; the Ashkenazi Jewish population contributing the highest point estimate has 29,222 observed alleles, exceeding the 2,000-allele minimum. gnomAD v2.1 likewise reports grpmax FAF 3.429e-05. The Ashkenazi Jewish point estimates (0.00680994 in v4.1 and 0.00617999 in v2.1) are not the permitted BA1 frequency measure and are also below 0.05.
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
BS1 is not met. The generic default threshold supplied for this case is >=0.01, and ClinGen SVI guidance requires the filtering grpmax FAF rather than a popmax point estimate for this frequency assessment. gnomAD v4.1 grpmax FAF is 2.169e-05 and gnomAD v2.1 grpmax FAF is 3.429e-05, both below 0.01. The Ashkenazi Jewish point estimates (0.00680994 in v4.1 and 0.00617999 in v2.1) are not the permitted BS1 measure and are also below the default. Therefore, no maximum-credible-frequency calculation is needed to override this negative frequency result.
Allele frequency is greater than expected for the disorder.
BS2 is not met. FANCC-associated Fanconi anemia is autosomal recessive, so this criterion would require observation of the variant in a healthy adult homozygote. gnomAD reports zero homozygotes in both gnomAD v2.1 (76 observed alleles; 281,922 total alleles) and gnomAD v4.1 (267 observed alleles; 1,556,608 total alleles). The available population data therefore provide no qualifying homozygous healthy-adult observation.
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
BP2 is not met. The available case report documents NM_000136.3:c.456+4A>T in trans with a FANCC deletion in an affected patient, but FANCC-associated Fanconi anemia is an autosomal-recessive disorder in this evidence. The documented trans configuration therefore supports PM3 rather than BP2, which requires trans observation in a fully penetrant dominant gene/disorder or cis observation with a pathogenic variant. No cis observation is reported.
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
Scope settled first: NM_000136.3:c.456+4A>T is an intronic/splice-region variant, so BP4 uses SpliceAI only; REVEL is not applicable and is not substituted. SpliceAI max delta is 0.895, which exceeds the supplied generic BP4 supporting threshold of <=0.1, so the prediction does not suggest no splice impact. The SpliceAI result is not double-counted from PP3.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
The available ClinVar record is Pathogenic, not Benign or Likely benign, and the submission audit reports zero expert-panel submissions. No exact-variant ClinVar expert-panel Benign/Likely benign classification is present. Ordinary laboratory submissions, aggregate labels, and literature without the required expert-panel status cannot trigger BP6.
Generic rules for PP5/BP6: apply them only for an exact-variant ClinVar expert-panel classification: Pathogenic/Likely pathogenic supports PP5; Benign/Likely benign supports BP6.
The governing ACMG/AMP rule requires a case-control prevalence comparison with RR or OR >5.0 and a confidence interval excluding 1.0. The reviewed material documents the exact variant in affected Fanconi anemia patients and includes a carrier-frequency paper, but it does not provide verified affected/control counts, an OR or RR, or a 95% CI. The literature_pass PS4 index names PMID:18197057, PMID:19888064, PMID:25394175, PMID:26389333, PMID:29939840, and PMID:8081385, but those papers were not present in paper_extracts.json or the fetched publications directory, so their abstracts or full texts could not be independently verified here. No numeric inequality can therefore be evaluated.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
PP1 cannot be assessed from the available evidence. The exact variant is reported in affected patient FA10, but the cited report provides no multiple affected family members carrying the variant, no informative meioses, and no segregation count sufficient to apply co-segregation evidence.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. ... May be used as stronger evidence with increasing segregation data.
The governing rule requires a patient's phenotype or family history highly specific for a disease with a single genetic etiology. The supplied case evidence identifies Fanconi anemia as the disease context but does not provide the patient's phenotype, family history, or a basis to show that the presentation is highly specific to FANCC rather than the genetically heterogeneous Fanconi anemia spectrum. PP4 therefore cannot be assessed from the available case-level phenotype data.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
No variant-specific functional study in the reviewed evidence demonstrates that FANCC c.456+4A>T has no damaging effect on protein function or splicing. The available variant-specific RNA result instead reports aberrant splicing, so it cannot establish BS3.
BS3
BS4 cannot be assessed. No affected family members with a negative genotype for FANCC c.456+4A>T are reported, and no family-level non-segregation analysis or phenotype assessment is available. The absence of such information is not evidence of lack of segregation.
Lack of segregation in affected members of a family.
The governing rule requires the variant to be found in a case with an alternate molecular basis for disease. The supplied evidence documents the FANCC variant and Fanconi anemia-related studies but provides no patient-level alternate pathogenic variant, molecular diagnosis, or case demonstrating another molecular basis for the phenotype. BP5 is therefore not assessed.
Variant found in a case with an alternate molecular basis for disease.
The variant is NM_000136.3:c.456+4A>T in the MANE Select FANCC transcript, annotated in intron 5 (exon 5i) with an unknown protein consequence. FANCC loss of function is supported as a disease mechanism, but this variant is at intronic position +4 and therefore is outside the governing PVS1 variant locations, which name canonical +/−1 or 2 splice sites rather than noncanonical +4 splice variants. Variant-specific RNA evidence shows abnormal FANCC transcripts, including exon 6 skipping or a 39-base exon 6 deletion, but that evidence does not change the named PVS1 applicability boundary. PVS1 is therefore not applicable, not a full-strength or downgraded PVS1 call.
PVS1: Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
The variant is NM_000136.3:c.456+4A>T with protein consequence p.? and is an intronic splice-region variant, not a missense amino-acid change; therefore the same-amino-acid comparison required for PS1 cannot apply, and the rule's splicing caveat is relevant.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
The variant is NM_000136.3:c.456+4A>T with protein consequence p.? and is intronic rather than a missense variant located at an amino-acid residue in a functional domain or mutational hotspot; PM1 therefore does not apply.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
The variant is intronic NM_000136.3:c.456+4A>T with an unknown protein consequence (NP_000127.2:p.?), not an in-frame deletion, in-frame insertion, or stop-loss variant. It therefore lies outside the variant types named by PM4.
PM4: Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
The variant is NM_000136.3:c.456+4A>T with protein consequence p.? and is an intronic splice-region variant, not a novel missense change at an amino-acid residue; the PM5 same-residue comparison is therefore outside the criterion's scope.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
The variant is NM_000136.3:c.456+4A>T with protein consequence p.? and is intronic rather than a missense variant, so the PP2 missense-gene-context criterion cannot be applied.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
The variant is NM_000136.3:c.456+4A>T with protein consequence p.? and is intronic rather than a missense variant, so the BP1 missense-gene-context criterion cannot be applied.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
The variant is intronic NM_000136.3:c.456+4A>T with an unknown protein consequence, not an in-frame deletion or insertion. No repetitive protein-coding region or protein-length change is involved, so the variant lies outside the BP3 variant type named by the rule.
BP3: In frame-deletions/insertions in a repetitive region without a known function.
BP7 is limited to synonymous variants. NM_000136.3:c.456+4A>T is intronic/splice-region, not synonymous, so BP7 is not applicable regardless of the available SpliceAI result or conservation evidence.
A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
Every interpreted variant in FANCC, mapped onto the exon structure of NM_000136.3. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| Ashkenazi Jewish199 / 29,222 | 0.0068 |
| Remaining individuals29 / 60,464 | 0.00048 |
| Admixed American3 / 59,918 | 5e-05 |
| European (non-Finnish)34 / 1,128,286 | 3e-05 |
| African/African American2 / 73,452 | 2.7e-05 |
| Ashkenazi Jewish64 / 10,356 | 0.0062 |
| Remaining individuals2 / 7,180 | 0.00028 |
| European (non-Finnish)9 / 128,782 | 7e-05 |
| Admixed American1 / 35,356 | 2.8e-05 |
This variant is present in gnomAD v4.1 (AF= 0.000171527; MAF= 0.01715%, 267/1556608 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00680994; MAF= 0.68099%, 199/29222 alleles, homozygotes = 0); grpmax FAF= 2.169e-05.
This variant is present in gnomAD v2.1 (AF= 0.000269578; MAF= 0.02696%, 76/281922 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00617999; MAF= 0.61800%, 64/10356 alleles, homozygotes = 0); grpmax FAF= 3.429e-05.
Not available in gnomAD-Canada v1.0.
Scope settled first: NM_000136.3:c.456+4A>T is an intronic/splice-region variant, so the generic rule requires the SpliceAI path only; REVEL is not applicable and is not used. SpliceAI reports DS_AG 0.000, DS_AL 0.375, DS_DG 0.481, and DS_DL 0.895, with max delta 0.895. This meets the supplied generic SpliceAI PP3 moderate threshold of >=0.5, calibrated by Jaganathan et al. 2019 (PMID:30661751). The same SpliceAI result is not double-counted for BP4 or BP7.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
Scope settled first: NM_000136.3:c.456+4A>T is an intronic/splice-region variant, so BP4 uses SpliceAI only; REVEL is not applicable and is not substituted. SpliceAI max delta is 0.895, which exceeds the supplied generic BP4 supporting threshold of <=0.1, so the prediction does not suggest no splice impact. The SpliceAI result is not double-counted from PP3.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
BP7 is limited to synonymous variants. NM_000136.3:c.456+4A>T is intronic/splice-region, not synonymous, so BP7 is not applicable regardless of the available SpliceAI result or conservation evidence.
A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
SpliceAI predicts possible splice impact for this variant (max delta score = 0.90).
8 paper records listed. 1 cited in the classification.
The only transcripts present were those that were alternatively spliced as a result of the paternal mutation c.45614A.T.
Location Table 1, FA10; Results, “A wide spectrum of FA gene mutations includes large deletions and duplications in FANCA, FANCB, FANCC, and FANCD2”; Figure 1A legend
Context FA10 from the International Fanconi Anemia Registry; FANCC genomic sequencing, aCGH to identify the deletion, and RT-PCR/RNA analysis to assess transcript expression and splicing.
The most common mutation is IVS4 + 4 A to T (IVS4), a splice mutation in intron 4, which has been found only in patients of Ashkenazi Jewish ancestry. When we screened 29 Japanese patients (20 unrelated patients and 4 families) using polymerase chain reaction
Abstract excerpt in literature_pass.json
Examples include FANCA variants among Spanish Gypsies (c.295C>T;p.Q99*) (Castella et al., 2011) and Japanese (c.2546delC) (Mori et al., 2019); FANCC variants among Ashkenazi Jews (c.456+4A>T) (Verlander et al., 1995) and Dutch/Manitoba Mennonites (c.67delG) (de Vries et al., 2012); and FANCG variants among the Portuguese-Brazilian (c.1077–2A>G), French-Acadian (c.1480+1G>C), and Korean/Japanese (c.307+1G>C) populations (Auerbach et al., 2003).
Introduction, paragraph 2
Fanconi anemia (FA) is a genetically and phenotypically heterogeneous autosomal recessive disorder defined by a cellular hypersensitivity to DNA cross-linking agents. One of the FA genes, FAC, has been cloned and the genomic structure of the coding region has been characterized. We have developed amplification refractory mutation system (ARMS) assays for five known mutations in FAC, and have appli
Abstract excerpt in literature_pass.json
We have amplified FACC exons with their flanking intron sequences from genomic DNA from 174 racially and ethnically diverse families in the International Fanconi Anemia Registry and have screened for mutations by using SSCP analysis. We identified eight different variants in 32 families; three were detected in exon 1, one in exon 4, one in intron 4, two in exon 6, and
Abstract excerpt in literature_pass.json
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 0.000171527; MAF= 0.01715%, 267/1556608 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00680994; MAF= 0.68099%, 199/29222 alleles, homozygotes = 0); grpmax FAF= 2.169e-05.
This variant is present in gnomAD v2.1 (AF= 0.000269578; MAF= 0.02696%, 76/281922 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 0.00617999; MAF= 0.61800%, 64/10356 alleles, homozygotes = 0); grpmax FAF= 3.429e-05.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (23 clinical laboratories). (ClinVarID = 12045)
SpliceAI predicts possible splice impact for this variant (max delta score = 0.90).
This variant has previously been reported in somatic cancers (COSMIC; COSV56656439, n = 1 times).