9-95101723-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong

The NM_000136.3(FANCC):c.1661T>C(p.Leu554Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,613,908 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L554L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

FANCC
NM_000136.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14O:2

Conservation

PhyloP100: 4.53

Publications

24 publications found

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 was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.947

PP5

Variant 9-95101723-A-G is Pathogenic according to our data. Variant chr9-95101723-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 12043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCC	NM_000136.3 link	c.1661T>C	p.Leu554Pro	missense_variant	Exon 15 of 15	ENST00000289081.8	NP_000127.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCC	ENST00000289081.8 link	c.1661T>C	p.Leu554Pro	missense_variant	Exon 15 of 15	1	NM_000136.3	ENSP00000289081.3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251192

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1461782

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727184

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53366

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

1111982

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41424

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000261

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group C

Pathogenic:8Other:1

Feb 01, 1993

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Dec 17, 2023

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 28, 2020

Leiden Open Variation Database

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:curation

Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -

Apr 23, 2019

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Oct 14, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: FANCC c.1661T>C (p.Leu554Pro) 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 1.2e-05 in 251192 control chromosomes (gnomAD). c.1661T>C has been reported in the literature in individuals affected with Fanconi Anemia (e.g. Strathdee_1992, Dokal_1996, Gillio_1997). These data indicate that the variant may be associated with disease. The variant has also been detected in at least one individual with bilateral breast cancer and a family history of the diseae (Thompson_2012). Several publications report experimental evidence evaluating an impact on protein function, reporting significantly reduced capacity for DNA repair and disruption of the protein's ability to bind FAA ( (e.g. Gavish_1993, Kupfer_1997, Donahue_2004). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014) and cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Feb 03, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 08, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 09, 2018

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not provided

Pathogenic:2Other:1

Nov 18, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The FANCC c.1661C>T (p.Leu554Pro) variant has been reported in the published literature in individuals with breast cancer (PMIDs: 23028338 (2012), 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/)), as well as head and neck squamous cell carcinoma (PMID: 28678401 (2017)). Additionally, this variant is associated with autosomal recessive Fanconi Anemia (FA) (PMIDs: 1574115 (1992)). In the published literature, this variant has been reported in multiple individuals with FA (PMIDs: 9207444 (1997), 8128956 (1994), 1574115 (1992)), most notably occurring in trans with an additional pathogenic FANCC variant (322delG) in two FA siblings (PMID: 8703809 (1996)). Experimental studies using FA patient derived cells suggest this variant is damaging to protein function, resulting in overexpression and increased MMC hypersensitivity (PMID: 8499901 (1993), 8613549 (1996)) failure to bind and/or interact with multiple proteins within the Fanconi Anemia complex (PMID: 9398857 (1997), 9242535 (1997), 10383195 (1999), 12093742 (2002), 12649160 (2003), 24469828 (2014), 26466335 (2015)), decreased double strand break repair and cell survival (PMID: 15364573 (2004)), and improper localization (PMID: 10383195 (1999)). The frequency of this variant in the general population, 0.000031 (4/128998 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Please note that these prediction tools are not fully validated, and therefore, should be viewed with caution. Due to the limited utility of current functional studies for heterozygous FANCC variants as well as unsupported FANCC heterozygote risk association with cancer, the experimental evidence mentioned above is viewed with caution at this time. Based on the available information, this variant is classified as a variant of unknown significance for cancer and likely pathogenic for Fanconi Anemia. -

SNPedia

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jul 15, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in individuals with breast and other cancers (Thompson et al., 2012; Chandrasekharappa et al., 2017); Published functional studies demonstrate a damaging effect: decreased capacity to tolerate mitomycin C and the inability to bind to FANCA, FANCE, and cdc2 (Gavish et al., 1993; Youssoufian et al., 1996; Kupfer et al., 1997a; Kupfer et al., 1997b; Gordon and Buchwald 2000); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.L553P; This variant is associated with the following publications: (PMID: 24469828, 28678401, 8703809, 8613549, 1574115, 12397061, 8499901, 9242535, 20301575, 26466335, 23028338, 9398857, 8128956, Gordon2000[Book]) -

Fanconi anemia

Pathogenic:2

Feb 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 554 of the FANCC protein (p.Leu554Pro). This variant is present in population databases (rs104886458, gnomAD 0.003%). This missense change has been observed in individual(s) with Fanconi anemia (PMID: 8703809, 11050007). 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: 12043). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects FANCC function (PMID: 8613549, 9242535, 9398857). For these reasons, this variant has been classified as Pathogenic. -

Mar 17, 2017

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

FANCC-related disorder

Pathogenic:1

Oct 03, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The FANCC c.1661T>C variant is predicted to result in the amino acid substitution p.Leu554Pro. This variant (originally identified as p.Leu553Pro) has been documented as being causative for Fanconi anemia (Strathdee et al 1992. PubMed ID: 157411) and may function in part by altering proper FANCC protein localization (Savoia et al. 1999. PubMed ID: 10383195). This variant is reported in 0.0031% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-97864005-A-G) and is interpreted as Pathogenic/Likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/12043/). This variant is interpreted as pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Apr 07, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.L554P pathogenic mutation (also known as c.1661T>C), located in coding exon 14 of the FANCC gene, results from a T to C substitution at nucleotide position 1661. The leucine at codon 554 is replaced by proline, an amino acid with similar properties. This alteration has been reported in trans with other loss-of-function FANCC alterations in patients with Fanconi Anemia (Strathdee CA et al. Nature 1992 Apr;356:763-7; Verlander PC et al. Am. J. Hum. Genet. 1994 Apr;54:595-601; Ambry internal data). Multiple defects in cells from one of these patients, who harbored FANCC c.322delG on the other chromosome, were rescued upon complementation with wild type constructs, however complementation with constructs harboring FANCC p.L554P were not able to rescue these defects. These defects include cell cycle regulation, sensitivity to chemical clastogens, subcellular localization, and binding to FANCA, FANCE and cdc2 (Gavish H et al. Hum. Mol. Genet. 1993 Feb;2:123-6; Dokal I et al. Br. J. Haematol. 1996 Jun;93:813-6; Youssoufian H et al. J. Clin. Invest. 1996 Feb;97:957-62; Kupfer GM et al. Blood 1997 Aug;90:1047-54; Kupfer GM et al. Nat. Genet. 1997 Dec;17:487-90; Savoia A et al. Blood 1999 Jun;93:4025-6; Pace P et al. EMBO J. 2002 Jul;21:3414-23; Gordon SM et al. Blood 2003 Jul;102:136-41). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.22

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

T;T

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.45

.;T

M_CAP

Benign

0.056

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Uncertain

-0.028

MutationAssessor

Uncertain

2.2

M;M

PhyloP100

4.5

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.9

D;D

REVEL

Uncertain

0.62

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.90

MVP

0.90

MPC

0.41

ClinPred

0.95

GERP RS

4.8

Varity_R

0.91

gMVP

0.83

Mutation Taster

=70/30

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over