ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.1544C>G (p.Thr515Ser) (rs201379302)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV001095337 SCV000481128 uncertain significance Fanconi anemia, complementation group C 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx RCV000519902 SCV000618177 uncertain significance not provided 2017-05-03 criteria provided, single submitter clinical testing This variant is denoted FANCC c.1544C>G at the cDNA level, p.Thr515Ser (T515S) at the protein level, and results in the change of a Threonine to a Serine (ACT>AGT). This variant has been observed in at least one individual with familial breast cancer (Thompson 2012). FANCC Thr515Ser was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Threonine and Serine share similar properties, this is considered a conservative amino acid substitution. FANCC Thr515Ser occurs at a position where amino acids with properties similar to Threonine are tolerated across species and is located within the CDC2 binding region (Gordon 2000). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether FANCC Thr515Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000284344 SCV000813912 uncertain significance Fanconi anemia 2019-09-26 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 515 of the FANCC protein (p.Thr515Ser). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and serine. This variant is present in population databases (rs201379302, ExAC 0.02%). This variant has not been reported in the literature in individuals with FANCC-related disease. ClinVar contains an entry for this variant (Variation ID: 367609). 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 serine 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.
Ambry Genetics RCV001012118 SCV001172535 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-29 criteria provided, single submitter clinical testing Insufficient evidence

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