rs104886457

chr9-95101742-G-Achr9-95101742-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000136.3(FANCC):c.1642C>T(p.Arg548Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000929 in 1,613,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000095 (0 hom.)
• Consequence: FANCC NM_000136.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18 O:2
• Conservation: PhyloP100: 0.389

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]

AOPEP (HGNC:1361): (aminopeptidase O (putative)) This gene encodes a member of the M1 zinc aminopeptidase family. The encoded protein is a zinc-dependent metallopeptidase that catalyzes the removal of an amino acid from the amino terminus of a protein or peptide. This protein may play a role in the generation of angiotensin IV. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Oct 2010]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-95101742-G-A is Pathogenic according to our data. Variant chr9-95101742-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95101742-G-A is described in Lovd as [Pathogenic]. Variant chr9-95101742-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCC	NM_000136.3	c.1642C>T	p.Arg548Ter	stop_gained	15/15	ENST00000289081.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCC	ENST00000289081.8	c.1642C>T	p.Arg548Ter	stop_gained	15/15	1	NM_000136.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152138 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000517 AC: 13 AN: 251222 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135816

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000951 AC: 139 AN: 1461806 Hom.: 0 Cov.: 31 AF XY: 0.000100 AC XY: 73 AN XY: 727190

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000110

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152138 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74318

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000121 Hom.: 0

Bravo AF: 0.0000982

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group C Pathogenic:13 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Apr 10, 2022	The c.1642C>T;p.(Arg548*) variant creates a premature translational stop signal in the FANCC gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 12047) - PS4. The variant is present at low allele frequencies population databases (rs104886457 – gnomAD 0.0004954%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic -
Likely pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Aug 19, 2022	The FANCC c.1642C>T (p.Arg548Ter) change is a nonsense variant that is predicted to cause premature protein truncation. The variant is not expected to result in nonsense mediated decay, but functional studies have demonstrated a damaging effect on FANCC function (PMID: 8882868). This variant has been reported in the homozygous or compound heterozygous state in multiple unrelated individuals affected with Fanconi anemia (PMID: 8103176, 28425259, 33960719). It has a maximum subpopulation frequency of 0.013% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 31, 2016	Variant summary: The c.1642C>T (p.Arg548*) variant in FANCC gene is a nonsense change predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay. The p.Arg548* is expected to lack last 11 amino acids and was unable to restore MMC hypersensitivity in the functional assay. The variant is present in the large control population dataset of ExAC at a low frequency 0.00002 (3/120522 chrs tested), which does not exceed the maximal expected frequency of a pathogenic allele (0.002) in this gene. The variant of interest has been reported in multiple affected individuals in homozygous or compound heterozygous state with a confirmed diagnosis of FA. Per multiple reports, this variant is strongly correlated with increased numbers of severe congenital malformation, earlier onsets of marrow failure, and overall poorer survival rate. In addition, multiple reputable databases/clinical laboratories classified this variant as Pathogenic. Taken together, the variant was classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
not provided, no classification provided	literature only	GeneReviews	-	Common in northern Europeans & southern Italy -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 31, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 06, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 11, 1993	- -
Pathogenic, criteria provided, single submitter	clinical testing	Daryl Scott Lab, Baylor College of Medicine	Feb 01, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 04, 2019	NM_000136.2(FANCC):c.1642C>T(R548*) is classified as likely pathogenic in the context of FANCC-related Fanconi anemia. Sources cited for classification include the following: PMID 9207444, 17924555, 8844212, 8882868 and 24469828. Classification of NM_000136.2(FANCC):c.1642C>T(R548*) is based on the following criteria: The variant causes a premature termination codon that is not expected to be targeted by nonsense-mediated mRNA decay; however, literature evidence strongly supports pathogenicity. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	Feb 28, 2020	Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Johan de Winter. -

Fanconi anemia Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 14, 2018	The p.Arg548X variant in FANCC has been identified in the homozygous or compound heterozygous state in more than 9 individuals with Fanconi anemia, and segregat ed with disease in at least 1 affected family member (Murer-Orlando 1993, Gillio 1997, Aftab 2017). This variant has also been identified in 8/111606 European c hromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstit ute.org; dbSNP rs104886457). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrie r frequency. This nonsense variant leads to a premature termination codon at pos ition 548. This alteration occurs within the last exon and is more likely to esc ape nonsense mediated decay (NMD) and result in a truncated protein. Nevertheles s, in vitro functional studies provide evidence that this variant disrupts FANCC function (Lo Ten Foe 1996). In summary, this variant meets criteria to be class ified as pathogenic for autosomal recessive Fanconi anemia. ACMG/AMP Criteria ap plied: PM3_Very Strong; PM4; PS3_Moderate. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change creates a premature translational stop signal (p.Arg548*) in the FANCC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 11 amino acid(s) of the FANCC protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Fanconi anemia (PMID: 8103176, 24584348). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12047). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects FANCC function (PMID: 8882868). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 26, 2020	Nonsense variant in the C-terminus predicted to result in protein truncation as the last 11 amino acids are lost; Published functional studies demonstrate a damaging effect: hypersensitivity to mitomycin C and inability to correct the cellular Fanconi anemia phenotype in transfected cells (Lo ten Foe 1996); Observed in the heterozygous state individuals with breast, gastric, or colon cancer (Slavin 2017, AlDubayan 2018, Drk 2019); This variant is associated with the following publications: (PMID: 12670332, 28139070, 28425259, 8103176, 8844212, 24584348, 20869034, 9207444, 27289500, 26681312, 29025585, 8348157, 17924555, 8882868, 29478780, 31467304, 29625052, 26689913) -
not provided, no classification provided	literature only	SNPedia	-	- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 15, 2022

The p.R548* pathogenic mutation (also known as c.1642C>T), located in coding exon 14 of the FANCC gene, results from a C to T substitution at nucleotide position 1642. This changes the amino acid from an arginine to a stop codon within coding exon 14. This mutation has been previously described in a compound heterozygous state in two unrelated patients with Fanconi Anemia (FA) (Aftab I et al. Turk. J. Med. Sci. 2017 Apr;47:391-398; Gibson RA et al. Hum. Mutat. 1996;8:140-8). This mutation has also been identified in a heterozygous state in individuals with breast cancer and/or colorectal cancer/polyps (Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; AlDubayan SH et al. Am. J. Hum. Genet. 2018 03;102(3):401-414). Functional studies have shown that cells transfected with this alteration are unable to correct the cellular phenotype of FA (Lo ten Foe JR et al. Hum. Genet. 1996 Nov;98:522-3). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	35
Dann	Uncertain	0.99
Eigen	Benign	0.16
Eigen_PC	Benign	-0.057
FATHMM_MKL	Benign	0.49	N
MutationTaster	Benign	1.0	A;A
Vest4		0.61
GERP RS		2.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs104886457; hg19: chr9-97864024; COSMIC: COSV56663862;