ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.1661T>C (p.Leu554Pro) (rs104886458)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000058925 SCV000512973 pathogenic not provided 2018-06-27 criteria provided, single submitter clinical testing This variant is denoted FANCC c.1661T>C at the cDNA level, p.Leu554Pro (L554P) at the proteinlevel, and results in the change of a Leucine to a Proline (CTG>CCG) in exon 15. This variant has observed in atleast two individuals with Fanconi Anemia (Verlander 1994). This variant was also identified in an individual with twoprimary breast cancers and a family history of breast cancer (Thompson 2012). Functional studies of this pathogenic variantresults in decreased capacity to tolerate mitomycin C and the inability to bind to FANCA, FANCE, and cdc2 (Gavish1993, Youssoufian 1996, Kupfer 1997a, Kupfer 1997b, Gordon 2003). FANCC Leu554Pro was not observed at asignificant allele frequency in the NHLBI Exome Sequencing Project. Since Leucine and Proline differ in someproperties, this is considered a semi-conservative amino acid substitution. FANCC Leu554Pro alters a position that ishighly conserved across species and is located in the cdc2 binding domain (Gordon 2000). In silico analyses predictthat this variant is probably damaging to protein structure and function. Based on the current evidence, we considerthis to be a pathogenic variant.
Baylor Genetics RCV000012823 SCV001163619 likely pathogenic Fanconi anemia, complementation group C criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000012823 SCV001363461 pathogenic Fanconi anemia, complementation group C 2019-10-14 criteria provided, single submitter clinical testing Variant summary: FANCC c.1661T>C (p.Leu554Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251192 control chromosomes (gnomAD). c.1661T>C has been reported in the literature in individuals affected with Fanconi Anemia (e.g. Strathdee_1992, Dokal_1996, Gillio_1997). These data indicate that the variant may be associated with disease. The variant has also been detected in at least one individual with bilateral breast cancer and a family history of the diseae (Thompson_2012). Several publications report experimental evidence evaluating an impact on protein function, reporting significantly reduced capacity for DNA repair and disruption of the protein's ability to bind FAA ( (e.g. Gavish_1993, Kupfer_1997, Donahue_2004). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014) and cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV001221431 SCV001393476 pathogenic Fanconi anemia 2019-07-30 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 554 of the FANCC protein (p.Leu554Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. This variant is present in population databases (rs104886458, ExAC 0.002%). This variant has been observed in individual(s) with Fanconi anemia (PMID: 11050007, 8703809). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 12043). This variant has been reported to affect FANCC protein function (PMID: 8613549, 9398857, 9242535). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000012823 SCV000033063 pathogenic Fanconi anemia, complementation group C 1993-02-01 no assertion criteria provided literature only
GeneReviews RCV000012823 SCV000057806 pathogenic Fanconi anemia, complementation group C 2016-09-22 no assertion criteria provided literature only
SNPedia RCV000058925 SCV000090446 not provided not provided no assertion provided not provided
Counsyl RCV000012823 SCV001132190 likely pathogenic Fanconi anemia, complementation group C 2018-10-09 no assertion criteria provided clinical testing
Leiden Open Variation Database RCV000012823 SCV001365344 pathogenic Fanconi anemia, complementation group C 2020-02-28 no assertion criteria provided curation Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.

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