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 2020-12-03 criteria provided, single submitter clinical testing Identified in two siblings with Fanconi anemia (Verlander 1994); Identified in individuals with breast and other cancers (Thompson 2012, Chandrasekharappa 2017); Published functional studies demonstrate a damaging effect: decreased capacity to tolerate mitomycin C and the inability to bind to FANCA, FANCE, and cdc2 (Gavish 1993, Youssoufian 1996, Kupfer 1997a, Kupfer 1997b, Gordon 2000); Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9398857, 8128956, 23028338, 26466335, 20301575, 9242535, 12397061, 8499901, 1574115, 8613549, 24469828, 28678401)
Baylor Genetics RCV000012823 SCV001163619 likely pathogenic Fanconi anemia, complementation group C criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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 2020-07-23 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 2021-06-01 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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