ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.973G>A (p.Ala325Thr) (rs201407189)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115364 SCV000149273 likely benign not specified 2017-09-28 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 RCV000197125 SCV000252623 benign Fanconi anemia 2020-12-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000575554 SCV000673312 benign Hereditary cancer-predisposing syndrome 2016-09-07 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Illumina Clinical Services Laboratory,Illumina RCV001169821 SCV001332598 likely benign 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000115364 SCV001361108 benign not specified 2019-12-23 criteria provided, single submitter clinical testing Variant summary: FANCC c.973G>A (p.Ala325Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00076 in 251484 control chromosomes, predominantly at a frequency of 0.01 within the East Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in FANCC causing Fanconi Anemia Group C phenotype (0.0018), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. In addition, a recent case-control association study involving breast and/or ovarian cancer patients and controls of Chinese ancestry (Pan_2019), found that the variant is not associated with a significant increase in breast/ovarian cancer risk. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as benign (2x) / likely benign (1x). Based on the evidence outlined above, the variant was classified as benign.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355026 SCV001549784 uncertain significance not provided no assertion criteria provided clinical testing The FANCC p.Ala325Thr variant was not identified in the literature nor was it identified in the Cosmic, MutDB, or LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs201407189) as “With Likely benign allele”, and in ClinVar (classified as benign by Invitae; classified as likely benign by GeneDx). The variant was identified in control databases in 200 (1 homozygous) of 277248 chromosomes at a frequency of 0.0007 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the East Asian population in 196 of 18870 chromosomes at a frequency greater than 1% (freq: 0.01). The p.Ala325 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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