ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.839C>T (p.Ser280Leu) (rs749230615)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484866 SCV000564976 uncertain significance not provided 2017-06-29 criteria provided, single submitter clinical testing This variant is denoted FANCC c.839C>T at the cDNA level, p.Ser280Leu (S280L) at the protein level, and results in the change of a Serine to a Leucine (TCG>TTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. FANCC Ser280Leu was observed at an allele frequency of 0.03% (3/8,640) in individuals of East Asian ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Serine and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. FANCC Ser280Leu occurs at a position that is not conserved and is located within the Hsp70 and GRP94 binding domains (Gordon 2000). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether FANCC Ser280Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Mendelics RCV000709087 SCV000838350 uncertain significance Fanconi anemia, complementation group C 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000988211 SCV001137848 uncertain significance Fanconi anemia, complementation group A 2019-05-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV001017686 SCV001178806 likely benign Hereditary cancer-predisposing syndrome 2019-01-30 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
Invitae RCV001243848 SCV001417032 uncertain significance Fanconi anemia 2019-09-27 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 280 of the FANCC protein (p.Ser280Leu). The serine residue is weakly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs749230615, ExAC 0.03%). This variant has not been reported in the literature in individuals with FANCC-related disease. ClinVar contains an entry for this variant (Variation ID: 418188). 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 leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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