rs104886459

Positions:

• chr9-95249224-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000136.3(FANCC):​c.67delG​(p.Asp23fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000212 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: FANCC NM_000136.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:19 O:2
• Conservation: PhyloP100: 2.11

Genes affected

FANCC (HGNC:3584): (FA complementation group C) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group C. [provided by RefSeq, Jul 2008]

FANCC (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 23 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-95249224-TC-T is Pathogenic according to our data. Variant chr9-95249224-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 12049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95249224-TC-T is described in Lovd as [Pathogenic]. Variant chr9-95249224-TC-T is described in Lovd as [Pathogenic]. Variant chr9-95249224-TC-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCC	NM_000136.3	c.67delG	p.Asp23fs	frameshift_variant	2/15	ENST00000289081.8	NP_000127.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCC	ENST00000289081.8	c.67delG	p.Asp23fs	frameshift_variant	2/15	1	NM_000136.3	ENSP00000289081.3

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000119 AC: 30 AN: 251226 Hom.: 0 AF XY: 0.000147 AC XY: 20 AN XY: 135764

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000220 AC: 321 AN: 1461838 Hom.: 0 Cov.: 31 AF XY: 0.000197 AC XY: 143 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000280

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74338

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000217 Hom.: 0

Bravo AF: 0.000121

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group C Pathogenic:8 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	May 17, 2024	This sequence variant is a single nucleotide deletion (delG) at position 67 of the coding sequence of the FANCC gene that results in an early termination signal 23 codons downstream of the frameshift at codon 23. Studies demonstrate that translation re-initiates at codon Met55, resulting in an amino-terminal truncated variant protein which retains all three functional domains (PMID: 8639804, 11520787). This is a previously reported variant (ClinVar 12049) that has been observed in homozygous or compound heterozygous state in many individuals and families affected by Fanconi anemia (PMID: 31044565, 22701786, 8639804, 9207444, 17924555, 8128956); this variant is additionally known as 322delG and delG322 in the literature. This variant is present in 342 of 1614016 alleles (0.02119%) in the gnomAD v4.1.0 population dataset. Functional studies indicate that the amino-truncated variant protein retains some residual, though reduced, enzymatic activity (PMID: 8639804). Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM2, PS3, PS4 -
not provided, no classification provided	literature only	GeneReviews	-	Common in northern Europeans & southern Italy -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 16, 2023	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 -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 19, 2019	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 07, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 04, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 02, 2016	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. -

not provided Pathogenic:7 Other:1

not provided, no classification provided	literature only	SNPedia	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 17, 2024	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; Also known as 322delG; This variant is associated with the following publications: (PMID: 8348157, 29399332, 29922827, 34761457, 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, 35417938, 36944283, 36451132, 31589614, 8734810, 32885271, Chan2021[article], 33471991, 22701786) -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 30, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	FANCC: PM3:Strong, PVS1:Strong, PS3:Moderate, PM2:Supporting -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 11, 2015	- -

Fanconi anemia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -

FANCC-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 18, 2024

The FANCC c.67delG variant is predicted to result in a frameshift and premature protein termination (p.Asp23Ilefs*23). This variant, which also has been referred to as c.322delG, has been previously reported as causative for Fanconi anemia and is a founder variant in the Dutch population (see for example Whitney et al. 1993. PubMed ID: 8348157; Mehta et al. 1993. PubMed ID: 20301575; Gillio et al. 1997. PubMed ID: 9207444; Gille et al. 2012. PubMed ID: 22778927). This variant is reported in 0.026% of alleles in individuals of European (Non-Finnish) descent in gnomAD, and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/12049/). Frameshift variants in FANCC are expected to be pathogenic. This variant is interpreted as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 02, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs104886459; hg19: chr9-98011506;