ClinVar Miner

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

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000224234 SCV000149256 likely benign not provided 2021-05-25 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 14695169, 23028338, 27621404, 24123366, 15695377)
Invitae RCV000197543 SCV000254258 likely benign Fanconi anemia 2020-12-02 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 In silico models in agreement (benign) ;Other data supporting benign classification;Other strong data;Other strong data supporting benign classification
Mendelics RCV000709095 SCV000838360 uncertain significance Fanconi anemia, complementation group C 2018-07-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000115347 SCV000917336 likely benign not specified 2020-11-19 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 0.00091 in 253266 control chromosomes. This frequency is lower than the estimated maximum frequency expected for a pathogenic variant in FANCC causing Fanconi Anemia Group C (0.00091 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, and head and neck squamous cell carcinoma, as well as in healthy controls (e.g. Seal_2003, Thompson_2012, Chandrasekharappa_2017, Couch_2005, Dudley_2018, Verhagen_2018, Hong_2018, Bonache_2018). These reports suggest that c.178G>A (legacy name 433G>A) is unlikely to be associated with these types of cancer, but do not provide unequivocal conclusions about association of the variant with Fanconi Anemia Group C. Co-occurrence with another pathogenic variant has been reported (BRCA2 c.5585_5588delTGAA, p.V1862fs*11; internal sample). 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). Nine other ClinVar submitters (evaluation after 2014) have cited the variant as likely benign (n=5) and uncertain significance (n=4). 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.
Baylor Genetics RCV000709095 SCV001482698 uncertain significance Fanconi anemia, complementation group C 2020-07-14 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Nilou-Genome Lab RCV000709095 SCV001653438 likely benign Fanconi anemia, complementation group C 2021-05-18 criteria provided, single submitter clinical testing
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.
Natera, Inc. RCV000709095 SCV001463023 uncertain significance Fanconi anemia, complementation group C 2017-11-14 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354572 SCV001549220 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The FANCC p.Val60Ile variant was identified in 4 of 1924 proband chromosomes (frequency: 0.002) from individuals or families with breast or pancreatic cancer and was present in 7 of 2384 control chromosomes (frequency: 0.003) from healthy individuals (Seal 2003, Couch 2005, Thompson 2012). The variant was identified in dbSNP (rs138629441) as “with other allele,” ClinVar (classified as likely benign by GeneDx, Ambry Genetics and 2 other submitters; and uncertain significance by Invitae and 2 other submitters) and LOVD 3.0 (observed 1x). The variant was identified in control databases in 237 of 276,496 chromosomes at a frequency of 0.0009, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 6 of 23,998 chromosomes (freq: 0.0003), Other in 6 of 6456 chromosomes (freq: 0.001), Latino in 21 of 34,398 chromosomes (freq: 0.0006), European in 181 of 126208 chromosomes (freq: 0.001434), Ashkenazi Jewish in 3 of 10,132 chromosomes (freq: 0.0003), East Asian in 1 of 18,836 chromosomes (freq: 0.00005), Finnish in 4 of 25,692 chromosomes (freq: 0.0002), and South Asian in 15 of 30,776 chromosomes (freq: 0.0005). The p.Val60 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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