ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.178G>A (p.Val60Ile) (rs138629441)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115347 SCV000149256 likely benign not specified 2017-10-09 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000197543 SCV000254258 likely benign Fanconi anemia 2019-12-30 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224234 SCV000281625 likely benign not provided 2015-08-19 criteria provided, single submitter clinical testing Converted during submission to Likely benign.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000224234 SCV000493642 uncertain significance not provided 2016-07-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000563479 SCV000673290 likely benign Hereditary cancer-predisposing syndrome 2018-10-26 criteria provided, single submitter clinical testing Other strong data;In silico models in agreement (benign) ;Other strong data supporting benign classification;Other data supporting benign classification
Mendelics RCV000709095 SCV000838360 uncertain significance Fanconi anemia, complementation group C 2018-07-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000115347 SCV000917336 likely benign not specified 2018-08-13 criteria provided, single submitter clinical testing Variant summary: FANCC c.178G>A (p.Val60Ile) 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 0.00088 in 279000 control chromosomes. This frequency is lower than expected for a pathogenic variant in FANCC causing Fanconi Anemia Group C (0.00088 vs 0.0018), allowing no conclusion about variant significance. c.178G>A has been reported in the literature in individuals affected with breast, prostate, pancreatic cancers, and head and neck squamous cell carcinoma as well as in healthy controls (Seal_2003, Thompson_2010, Chandrasekharappa_2017, Couch_2005). These report(s) suggest that c.178G>A (legacy name 433G>A) is unlikely to be associated with these type of cancer, but do not provide unequivocal conclusions about association of the variant with Fanconi Anemia Group C. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported, but multiple authors consider the variant as neutral polymorphism (Savoia_1996; Verhagen_2018). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Likely benign 3X; VUS 2X). Based on the evidence outlined above, the variant was classified as Likely Benign.
Mendelics RCV000988221 SCV001137858 uncertain significance Fanconi anemia, complementation group A 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000709095 SCV001329923 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.
Leiden Open Variation Database RCV000224234 SCV001365311 uncertain significance not provided 2020-02-28 no assertion criteria provided curation Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.

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