ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.817G>A (p.Glu273Lys) (rs143181565)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160481 SCV000211046 uncertain significance not provided 2018-03-19 criteria provided, single submitter clinical testing This variant is denoted FANCC c.817G>A at the cDNA level, p.Glu273Lys (E273K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant, also denoted 1072G>A, has been observed in 1/421 pancreatic cancer cases and 3/654 controls with no personal history of colon or pancreatic cancer (Couch 2005). FANCC Glu273Lys was observed at an allele frequency of 0.02% (28/126,662) in individuals of European ancestry in large population cohorts (Lek 2016). FANCC Glu273Lys is located in the region of interaction with GRP94 and Hsp70 (Gordon 2000). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether FANCC Glu273Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV001085038 SCV000254264 likely benign Fanconi anemia 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000571755 SCV000673297 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-22 criteria provided, single submitter clinical testing Insufficient evidence
Mendelics RCV000709088 SCV000838351 uncertain significance Fanconi anemia, complementation group C 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000988212 SCV001137849 uncertain significance Fanconi anemia, complementation group A 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000709088 SCV001328092 uncertain significance Fanconi anemia, complementation group C 2018-01-13 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.
Integrated Genetics/Laboratory Corporation of America RCV001194155 SCV001363459 uncertain significance not specified 2019-01-25 criteria provided, single submitter clinical testing Variant summary: The variant, FANCC c.817G>A (p.Glu273Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 278450 control chromosomes (gnomAD and Couch_2005). This frequency is not significantly higher than expected for a pathogenic variant in FANCC causing Fanconi Anemia Group C (0.00014 vs 0.0018), allowing no conclusion about variant significance. The variant, c.817G>A has been reported in the literature in individuals affected with pancreatic cancer, Fanconi Anemia Group C, and GBM (Couch_2005, Li_2018. Lu_2015). These reports do not provide unequivocal conclusions about association of the variant with Fanconi Anemia Group C. The variant of interest was functionally assessed and found to have no impact on expression and rescued MMC sensitivity. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant three times as uncertain significance and once as likely benign. Based on the evidence outlined above, the variant was classified as VUS - possibly benign.

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