rs121917783

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000136.3(FANCC):c.553C>T(p.Arg185Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000164 in 1,613,952 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

FANCC
NM_000136.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 1.70

Variant links:

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 links:

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]

AOPEP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 9-95150056-G-A is Pathogenic according to our data. Variant chr9-95150056-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 12044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95150056-G-A is described in Lovd as [Pathogenic]. Variant chr9-95150056-G-A is described in Lovd as [Pathogenic]. Variant chr9-95150056-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCC	NM_000136.3 linkuse as main transcript	c.553C>T	p.Arg185Ter	stop_gained	7/15	ENST00000289081.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCC	ENST00000289081.8 linkuse as main transcript	c.553C>T	p.Arg185Ter	stop_gained	7/15	1	NM_000136.3	P1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251400

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135862

show subpopulations

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000170

AC:

248

AN:

1461876

Hom.:

Cov.:

AF XY:

0.000177

AC XY:

129

AN XY:

727238

show subpopulations

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:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000217

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.000112

AC:

AN:

152076

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74276

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.000221

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000161

Hom.:

Bravo

AF:

0.000121

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group C

Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 15, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 03, 2017	Variant summary: The FANCC c.553C>T (p.Arg185X) variant involves the alteration of a non-conserved nucleotide, resulting in a nonsense codon. One in silico tool predicts a damaging outcome for this variant. This variant was found in the large control database ExAC at a frequency of 0.0000414 (5/120748 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic FANCC variant (0.0017678). Several reports in the literature have detected the variant among individuals diagnosed with a variety of cancers, including 2 families where the variant segregated with disease in 4 individuals (Verlander_AJHG_1994). Functional studies have revealed that the variant causes partial skip of exon 6 and is predicted to result in frameshit in cell culture via cDNA analysis (Palagyi_MC_2010). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 06, 2021	- -

Fanconi anemia

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	May 20, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 13, 2024	This sequence change creates a premature translational stop signal (p.Arg185*) in the FANCC gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs121917783, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with breast and/or ovarian cancer and Fanconi anemia (PMID: 7689011, 8128956, 17924555, 22778927, 23028338, 23613520, 26681312). ClinVar contains an entry for this variant (Variation ID: 12044). Studies have shown that this premature translational stop signal results in skipping of 7, but is expected to preserve the integrity of the reading-frame (PMID: 7689011, 20509860). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 03, 2022	Predicted to result in protein truncation or nonsense mediated decay, either by premature stop or splice defect, in a gene for which loss-of-function is a known mechanism of disease (Gibson 1993, Belanger 2013); Published functional studies demonstrate a damaging effect: skipping of the in-frame exon 7, impaired protein migration, and reduced ability to repair DNA interstrand crosslinks (Gibson 1993, Belanger 2013); Observed in the homozygous and compound heterozygous state in patients with Fanconi anemia in published literature (Gibson 1993, Tsangaris 2011, Gille 2012); Observed in the heterozygous state in individuals with FANCC-related cancers (Thompson 2012, Schrader 2016, Melloni 2017, Dork 2019); This variant is associated with the following publications: (PMID: 25525159, 12670332, 21659346, 23028338, 28259476, 26681312, 29416752, 26689913, 20509860, 22778927, 27577878, 30322717, 28125078, 7746424, 26556299, 31467304, 28569218, 7689011, 29625052, 32885271, 32427313) -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Malignant tumor of breast

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The FANCC p.Arg185* variant was identified in 8 of 20760 proband chromosomes (frequency: 0.0004) from individuals or families with breast cancer or as co-occurring with a pathogenic variant in FANCC in compound heterozygous individuals with Fanconi anemia (Ameziane 2008, Chandasekharappa 2013, Gille 2012, Susswein 2015, Thompson 2012, Verlander 1994). The variant was also identified in dbSNP (ID: rs121917783) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, GeneDx, Ambry Genetics, and two other clinical laboratories), and LOVD 3.0 (18x). The variant was not identified in the Cosmic database. The variant was identified in control databases in 19 of 277128 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 17 of 126654 chromosomes (freq: 0.0001), African in 1 of 24014 chromosomes (freq: 0.00004), and South Asian in 1 of 30778 chromosomes (freq: 0.00003), but not in the Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Arg185* variant leads to a premature stop codon at position 185, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the FANCC gene are an established mechanism of disease in FANCC-associated cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2021

The p.R185* pathogenic mutation (also known as c.553C>T), located in coding exon 6 of the FANCC gene, results from a C to T substitution at nucleotide position 553. This changes the amino acid from an arginine to a stop codon within coding exon 6. This mutation has been identified homozygous and compound heterozygous in several Fanconi anemia cohorts (Gibson RA et al. Hum. Mol. Genet. 1993 Jun;2:797-9; Ameziane N et al. Hum. Mutat. 2008 Jan;29:159-66; Gille JJ et al. Anemia. 2012 Jun;2012:603253; Tsangaris E et al. J. Med. Genet. 2011 Sep;48:618-28) and was not detected in 70 unrelated British controls (Gibson RA et al. Hum. Mol. Genet. 1993 Jun;2:797-9). This mutation has also been reported in individuals with breast cancer and a family history of breast and/or ovarian cancer (Thompson ER et al. PLoS Genet. 2012 Sep;8:e1002894; Susswein LR et al. Genet. Med. 2016 08;18:823-32). Of note, this alteration is also designated as 808C>T 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

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.55

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Uncertain

0.33

Eigen_PC

Benign

0.10

FATHMM_MKL

Benign

0.63

MutationTaster

Benign

1.0

A;A

Vest4

0.93

GERP RS

2.9

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.31

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.31

Position offset: -31

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over