Submissions for variant NM_000136.3(FANCC):c.67del (p.Asp23fs)

dbSNP: rs104886459

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000058926	SCV000149267	pathogenic	not provided	2022-01-04	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 8348157, 29399332, 23028338, 8128956, 17924555, 1574115, 17909071, 22778927, 26466335, 8639804, 21659346, 27165789, 27133164, 26976241, 15695377, 27577878, 26681312, 27832981, 28717661, 28425259, 8703809, 28125075, 7746424, 29269525, 29849115, 29767408, 30322717, 31044565, 20507306, 11110674, 9207444, 11520787, 29625052, 26689913, 31263571, 31589614, 8734810, 32885271, Chan2021[article], 22701786)
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000058926	SCV000280699	pathogenic	not provided	2015-02-11	criteria provided, single submitter	clinical testing
Invitae	RCV000460906	SCV000549966	pathogenic	Fanconi anemia	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp23Ilefs*23) in the FANCC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FANCC are known to be pathogenic (PMID: 17924555). This variant is present in population databases (rs104886459, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 8128956, 9207444, 11110674, 17909071, 20301575, 22701786, 22778927, 23028338). It is commonly reported in individuals of Dutch ancestry (PMID: 8128956, 9207444, 11110674, 17909071, 20301575, 22701786, 22778927, 23028338). This variant is also known as 322delG. ClinVar contains an entry for this variant (Variation ID: 12049). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000012829	SCV000695436	pathogenic	Fanconi anemia complementation group C	2016-09-02	criteria provided, single submitter	clinical testing	Variant summary: The FANCC c.67delG (p.Asp23Ilefs) variant results in a premature termination codon, predicted to cause a truncated or absent FANCC protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 8/121184 control chromosomes at a frequency of 0.000066, which does not exceed the estimated maximal expected allele frequency of a pathogenic FANCC variant (0.0017678). The variant is a common disease variant reported in numerous affected individuals in the literature in the homozygous and compound heterozygous state. It has been reported that individuals homozygous for the variant have milder phenotypes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Baylor Genetics	RCV000012829	SCV001163261	pathogenic	Fanconi anemia complementation group C		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001025667	SCV001187905	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-02	criteria provided, single submitter	clinical testing	The c.67delG pathogenic mutation, located in coding exon 1 of the FANCC gene, results from a deletion of one nucleotide at nucleotide position 67, causing a translational frameshift with a predicted alternate stop codon (p.D23Ifs*23). This mutation has been identified in numerous patients with Fanconi anemia (FA) in both a compound heterozygous and homozygous state (Verlander PC et al. Am. J. Hum. Genet. 1994 Apr;54:595-601; Gillio AP et al. Blood. 1997 Jul;90:105-10; Faivre L et al. Blood. 2000 Dec;96:4064-70; Ameziane N et al. Hum. Mutat. 2008 Jan;29:159-66; Gille JJ et al. Anemia. 2012 Jun;2012:603253; Sumpter R et al. Cell. 2016 May;165:867-81; Aftab I et al. Turk. J. Med. Sci. 2017 Apr;47:391-398). Haplotype analysis suggests this mutation is likely a Dutch founder mutation, and while FA patients homozygous for this mutation often show a more mild FA phenotype, clinical variability can be seen (de Vries Y et al. Anemia. 2012 Jun;2012:865170). Functional analysis has shown this alteration failed to rescue nuclear DNA damage repair functions of FANCC but was as effective as wild type FANCC in decreasing cytokine hypersensitivity (Sumpter R et al. Cell. 2016 May;165:867-81). This mutation has also been reported in a heterozygous state in several individuals diagnosed with breast cancer (Berwick M et al. Cancer Res. 2007 Oct;67:9591-6; Thompson ER et al. PLoS Genet. 2012 Sep;8:e1002894; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32). Of note, this alteration is also designated as 322delG in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV000012829	SCV001193815	pathogenic	Fanconi anemia complementation group C	2019-12-19	criteria provided, single submitter	clinical testing	NM_000136.2(FANCC):c.67delG(D23Ifs*23) is classified as pathogenic in the context of FANCC-related Fanconi anemia, and is associated with a mild form of the disease. Sources cited for classification include the following: PMID 22701786, 9207444, 17924555, 8128956, 8639804, 11520787, 1641028 and 8348157. Classification of NM_000136.2(FANCC):c.67delG(D23Ifs*23) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000012829	SCV002769464	pathogenic	Fanconi anemia complementation group C	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Fanconi anemia, complementation group C (MIM#227645). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 33 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported as pathogenic in individuals with Fanconi anemia, complementation group C (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in ClinVar. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV000012829	SCV002810898	pathogenic	Fanconi anemia complementation group C	2022-05-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000058926	SCV004032859	pathogenic	not provided	2023-07-01	criteria provided, single submitter	clinical testing	FANCC: PM3:Strong, PVS1:Strong, PS3:Moderate, PM2:Supporting
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000058926	SCV004218688	pathogenic	not provided	2022-09-30	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the FANCC mRNA and causes the premature termination of FANCC protein synthesis. In the published literature, the variant has been reported in affected individuals with Fanconi anemia (PMIDs: 8348157 (1993), 9207444 (1997), 11110674 (2000), 20507306 (2010), 22701786 (2012), 22778927 (2012), and 28425259 (2017)), breast cancer (PMIDs: 17909071 (2007), 23028338 (2012), 26681312 (2015), 29767408 (2018)), as well as in breast cancer cases and control individuals in a large scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/FANCC)). Functional studies showed that this variant rescued cytokine hypersensitivity, but failed to rescue nuclear DNA damage repair functions of FANCC (PMID: 27133164 (2016)). Based on the available information, this variant is classified as pathogenic.
OMIM	RCV000012829	SCV000033069	pathogenic	Fanconi anemia complementation group C	2001-09-01	no assertion criteria provided	literature only
GeneReviews	RCV000012829	SCV000057810	not provided	Fanconi anemia complementation group C		no assertion provided	literature only	Common in northern Europeans & southern Italy
SNPedia	RCV000058926	SCV000090447	not provided	not provided		no assertion provided	not provided
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000012829	SCV001551603	pathogenic	Fanconi anemia complementation group C		no assertion criteria provided	clinical testing	The FANCC p.Asp23IlefsX23 variant was identified in 15 (7 homozygous) of 1374 proband chromosomes (frequency: 0.021) from Dutch, Italian and Australian individuals or families with Fanconi-Anemia and non-BRCA1/2 familial breast cancer (Ameziane 2008, Gille 2012, de Rocco 2014, Thompson 2012). Further, the variant was observed to co-occur with pathogenic FANCC variants: 844-1G>C, c.553C>T/p.Arg185X, c.1155-1G>C splice, c.467delC/p.Ser156fs in Fanconi anemia families and with a familial BRCA2 pathogenic variant (c.8297delC, p.Thr2766Asnfs*11) in 1 breast cancer family. The variant was also identified in the following databases: dbSNP (ID: rs104886459) “With Pathogenic allele”, ClinVar (classified pathogenic by GeneDx, Invitae, OMIM, GeneReviews, Center for Pediatric Genomic Medicine (Children's Mercy Hospital and Clinics) and classification not provided by SNPedia), Clinvitae (3x), LOVD 3.0 (59x); it was not identified in Cosmic or MutDB. The variant was identified in control databases in 34 of 276940 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European (Non-Finnish) population in 34 of 126464 chromosomes (freq: 0.0003); it was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), Latino, Other, and South Asian populations. The c.67delG variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 23 and leads to a premature stop codon 23 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the FANCC gene are an established mechanism of disease in Fanconi Anemia; the relationship between this type of variant and hereditary breast and ovarian cancer, is not well understood. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000058926	SCV001807437	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000058926	SCV001972795	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000058926	SCV002036477	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000460906	SCV002081313	pathogenic	Fanconi anemia	2017-03-17	no assertion criteria provided	clinical testing