chr9-95249289-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PS1_ModeratePM2
The NM_000136.3(FANCC):c.3G>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000684 in 1,461,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
FANCC
NM_000136.3 start_lost
NM_000136.3 start_lost
Scores
8
5
2
Clinical Significance
Conservation
PhyloP100: 5.31
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 12 ACMG points.
PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in NM_000136.3 (FANCC) was described as [Likely_pathogenic] in ClinVar as 557034
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FANCC | NM_000136.3 | c.3G>A | p.Met1? | start_lost | 2/15 | ENST00000289081.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FANCC | ENST00000289081.8 | c.3G>A | p.Met1? | start_lost | 2/15 | 1 | NM_000136.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461770Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727192
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 07, 2021 | The p.M1? pathogenic mutation (also known as c.3G>A) is located in coding exon 1 of the FANCC gene and results from a G to A substitution at nucleotide position 3. This alters the methionine residue at the initiation codon (ATG). Sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 15, 2022 | Variant summary: FANCC c.3G>A (p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon; the next in-frame Methionine occurs at codon 16 in the native protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250170 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3G>A has been reported in the literature in at least one individual affected with Head and Neck Squamous Cell Carcinoma (Chandrasekharappa_2017). This report does not provide unequivocal conclusions about association of the variant with Fanconi Anemia Group C. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters have assessed the variant since 2014: both classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Fanconi anemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 01, 2021 | This sequence change affects the initiator methionine of the FANCC mRNA. The next in-frame methionine is located at codon 16. This variant is not present in population databases (ExAC no frequency). Disruption of the initiator codon has been observed in individual(s) with head and neck cancer (PMID: 28678401). ClinVar contains an entry for this variant (Variation ID: 632544). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. - |
Fanconi anemia complementation group C Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 17, 2018 | The FANCC c.3G>A (p.Met1?) variant is predicted to disrupt the initiator codon, and may interfere with protein expression. The p.Met1? variant has not been reported in the literature in association with Fanconi anemia but was identified in an individual with head and neck squamous cell carcinoma (Chandrasekharappa et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.000009 in the European (non-Finnish) population of the Genome Aggregation Database. However, this frequency is based on one allele only, so the variant is presumed to be rare. Based on the variant frequency and the disease prevalence, penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Due to the potential impact on protein expression and the lack of clarifying evidence, the p.Met1? variant is classified as a variant of unknown significance but suspicious for pathogenicity for Fanconi anemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;D;T;.;T;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
T
MutationTaster
Benign
D;D
PROVEAN
Uncertain
D;D;.;.;D;.;.;.
REVEL
Uncertain
Sift
Pathogenic
D;D;.;.;D;.;.;.
Sift4G
Pathogenic
D;D;D;.;D;.;.;.
Polyphen
D;D;.;.;D;.;.;.
Vest4
MutPred
Gain of catalytic residue at M1 (P = 0.0409);Gain of catalytic residue at M1 (P = 0.0409);Gain of catalytic residue at M1 (P = 0.0409);Gain of catalytic residue at M1 (P = 0.0409);Gain of catalytic residue at M1 (P = 0.0409);Gain of catalytic residue at M1 (P = 0.0409);Gain of catalytic residue at M1 (P = 0.0409);Gain of catalytic residue at M1 (P = 0.0409);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at