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

gnomAD frequency: 0.00028  dbSNP: rs201407189

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001355026	SCV000149273	benign	not provided	2018-08-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28863211, 28767289)
Invitae	RCV000197125	SCV000252623	benign	Fanconi anemia	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000575554	SCV000673312	benign	Hereditary cancer-predisposing syndrome	2016-09-07	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Illumina Laboratory Services, 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.
Sema4, Sema4	RCV000197125	SCV002535128	benign	Fanconi anemia	2021-11-15	criteria provided, single submitter	curation
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001169821	SCV004017620	benign	Fanconi anemia complementation group C	2023-07-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003905096	SCV004727362	benign	FANCC-related disorder	2019-07-31	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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.
Natera, Inc.	RCV000197125	SCV002081198	likely benign	Fanconi anemia	2017-05-16	no assertion criteria provided	clinical testing