Submissions for variant NM_000136.3(FANCC):c.77C>T (p.Ser26Phe)

gnomAD frequency: 0.00511  dbSNP: rs1800361

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000120974	SCV000168418	benign	not specified	2013-10-24	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.
Eurofins Ntd Llc (ga)	RCV000120974	SCV000227022	benign	not specified	2014-12-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001083879	SCV000262160	benign	Fanconi anemia	2024-02-01	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000120974	SCV000296873	benign	not specified	2015-10-11	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120974	SCV000594675	benign	not specified	2021-11-08	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000513630	SCV000609344	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	FANCC: BP4, BS2
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000513630	SCV000609628	likely benign	not provided	2017-08-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000573438	SCV000673289	likely benign	Hereditary cancer-predisposing syndrome	2018-08-31	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120974	SCV000917335	benign	not specified	2018-06-05	criteria provided, single submitter	clinical testing	Variant summary: FANCC c.77C>T (p.Ser26Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0049 in 276964 control chromosomes in the gnomAD database, including 8 homozygotes. The observed variant frequency is approximately 3-folds higher than 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 benign. The variant, c.77C>T, was observed in a family, which did not segregate with disease (affected sibling lacking the variant (Verlander_1994).To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign.
Mendelics	RCV000988227	SCV001137864	likely benign	Fanconi anemia complementation group A	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001168031	SCV001330588	uncertain significance	Fanconi anemia complementation group C	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genome-Nilou Lab	RCV001168031	SCV001652743	benign	Fanconi anemia complementation group C	2021-05-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000120974	SCV002046770	benign	not specified	2021-04-02	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV001083879	SCV002535122	likely benign	Fanconi anemia	2021-04-30	criteria provided, single submitter	curation
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001168031	SCV004017606	benign	Fanconi anemia complementation group C	2023-07-07	criteria provided, single submitter	clinical testing
ITMI	RCV000120974	SCV000085142	not provided	not specified	2013-09-19	no assertion provided	reference population
PreventionGenetics, part of Exact Sciences	RCV003891642	SCV000302522	benign	FANCC-related disorder	2020-02-03	no assertion criteria provided	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).
Leiden Open Variation Database	RCV000513630	SCV001365308	uncertain significance	not provided	2020-02-28	flagged submission	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357504	SCV001552990	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The FANCC p.Ser26Phe variant was identified in 15 of 1470 proband chromosomes (frequency: 0.01) from British and American individuals or families with BRCA1/2 negative breast cancer, pancreatic cancer or leukemias (AML and ALL) and was present in 10 of 2270 control chromosomes (frequency: 0.004) from healthy individuals (Seal 2003, Barber 2003, Couch 2005, Rogers 2004). The variant did not cosegregate with disease in family members with pancreatic cancer, lymphoma or breast cancer in one study (Rogers 2004); was observed 4X greater in sporadic childhood AML patients vs those with ALL in another study (Barber 2003). The variant was also identified in dbSNP (ID: rs1800361) “With other allele”, ClinVar (classified as benign by GeneDx, EGL Genetic Diagnostics(Eurfins Clinical Diagnostics), Invitae, Div. of Genomic Diagnostics (Children's Hospital of Philadelphia); likely benign by Prevention Genetics and classification not provided by ITMI ), Clinvitae (3x), LOVD 3.0 (1x), and was not identified in Cosmic, and MutDB databases. The variant was identified in control databases in 1365 (8 homozygous) of 276964 chromosomes at a frequency of 0.005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017), being identified in the following populations: African in 22 (1 homozygous) of 24038 chromosomes (frequency: 0009), Other in 41 of 6462 chromosomes (frequency: 006), Latino in 143 of 34416 chromosomes (frequency: 004), European Non-Finnish in 873 (5 homozygous) of 126482 chromosomes (frequency: 007), Ashkenazi Jewish in 91 of 10144 chromosomes (frequency: 009), European Finnish in 134 (2 homozygous) of 25784 chromosomes (frequency: 005), South Asian in 61 of 30780 chromosomes (frequency: 002), The variant was also identified by our laboratory in 1 individual with breast cancer, co-occurring with a pathogenic BRCA2 mutation (c.8195T>A, p.2732X). The p.Ser26 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Phe variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000120974	SCV001808201	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000513630	SCV001969055	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000513630	SCV002036533	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001083879	SCV002081312	likely benign	Fanconi anemia	2018-03-21	no assertion criteria provided	clinical testing