rs730881717
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_000136.3(FANCC):c.792T>G(p.Ser264Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000136.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FANCC | NM_000136.3 | c.792T>G | p.Ser264Arg | missense_variant | 8/15 | ENST00000289081.8 | NP_000127.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FANCC | ENST00000289081.8 | c.792T>G | p.Ser264Arg | missense_variant | 8/15 | 1 | NM_000136.3 | ENSP00000289081.3 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152162Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251446Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135900
GnomAD4 exome AF: 0.0000294 AC: 43AN: 1461764Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 21AN XY: 727178
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152162Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74338
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 08, 2021 | Variant summary: FANCC c.792T>G (p.Ser264Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251446 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.792T>G has been reported in the literature in an individual affected with childhood T-cell acute lymphoblastic leukemia (Burns_2018, Pouliot_2019) and in a prostate cancer tumor sample (Mateo_2020), however it is unclear whether the variant was somatic or germline occurrence in these cases. In a large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC) the variant was reported in 4/60466 cases and 8/53461 controls (Dorling_2021 through LOVD). These reports do not provide unequivocal conclusions about association of the variant with Fanconi Anemia Group C. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated a hypomorphic effect (about 75-80% of the wild-type function) based on viability, ability to rescue G2/M arrest, and efficiency in reducing radial chromosome formation after treatment with DNA cross-linking agents (Pouliot_2019). Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 01, 2020 | DNA sequence analysis of the FANCC gene demonstrated a sequence change, c.792T>G, in exon 8 that results in an amino acid change, p.Ser264Arg. This sequence change does not appear to have been previously described in patients with FANCC-related disorders and has been described in the gnomAD database with a low population frequency of 0.0079% in the non-Finnish European subpopulations (dbSNP rs730881717). The p.Ser264Arg change affects a moderately conserved amino acid residue located in a domain of the FANCC protein that is known to be functional. The p.Ser264Arg substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ser264Arg change remains unknown at this time. - |
Fanconi anemia Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 01, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 19, 2022 | This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 264 of the FANCC protein (p.Ser264Arg). This variant is present in population databases (rs730881717, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with FANCC-related conditions. ClinVar contains an entry for this variant (Variation ID: 182477). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on FANCC function (PMID: 31721781). 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 17, 2024 | In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Published functional studies suggest no damaging effect: mRNA expression, radial chromosome formation and relative viability after exposure to Mitomycin C, and ability to rescue G2/M arrest were all comparable to wildtype (PMID: 31721781); This variant is associated with the following publications: (PMID: 30404791, 31721781, Gordon2000[Book], 33471991, 29654263, 31874108, 32885271) - |
Fanconi anemia complementation group C Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 30, 2021 | - - |
Malignant tumor of breast Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The FANCC p.Ser264Arg variant was identified in 1 of 218 proband chromosomes (frequency: 0.005) from T-cell acute lymphoblastic leukemia clinical samples (Burns 2018). The variant was identified in dbSNP (rs730881717) as “with uncertain significance allele” and ClinVar (classified as uncertain significance by Invitae, GeneDx and Integrated Genetics). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 9 of 251,446 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 9 of 113,742 chromosomes (freq: 0.00008); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, Finnish, Other or South Asian populations. The p.Ser264 residue is conserved in in mammals but not in more distantly related organisms however 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. - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 25, 2024 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at