rs1800365

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000136.3(FANCC):c.584A>T(p.Asp195Val) variant causes a missense change. The variant allele was found at a frequency of 0.00394 in 1,614,040 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0029 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0041 ( 25 hom. )

Consequence

FANCC
NM_000136.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:23O:1

Conservation

PhyloP100: 4.53

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 Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.027212769).

BP6

Variant 9-95150025-T-A is Benign according to our data. Variant chr9-95150025-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134305.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=9, Benign=9, Uncertain_significance=3, not_provided=1}. Variant chr9-95150025-T-A is described in Lovd as [Likely_benign]. Variant chr9-95150025-T-A is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAdExome4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCC	NM_000136.3 link	c.584A>T	p.Asp195Val	missense_variant	Exon 7 of 15	ENST00000289081.8	NP_000127.2	Q00597A0A024R9N2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCC	ENST00000289081.8 link	c.584A>T	p.Asp195Val	missense_variant	Exon 7 of 15	1	NM_000136.3	ENSP00000289081.3		Q00597

Frequencies

GnomAD3 genomes

AF:

0.00286

AC:

435

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000628

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00321

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.000755

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00469

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00313

AC:

787

AN:

251330

Hom.:

AF XY:

0.00319

AC XY:

433

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.00263

Gnomad ASJ exome

AF:

0.00377

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00333

Gnomad FIN exome

AF:

0.000323

Gnomad NFE exome

AF:

0.00464

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00406

AC:

5932

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00413

AC XY:

3002

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.000777

Gnomad4 AMR exome

AF:

0.00280

Gnomad4 ASJ exome

AF:

0.00314

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00344

Gnomad4 FIN exome

AF:

0.000543

Gnomad4 NFE exome

AF:

0.00453

Gnomad4 OTH exome

AF:

0.00508

GnomAD4 genome

AF:

0.00286

AC:

435

AN:

152182

Hom.:

Cov.:

AF XY:

0.00263

AC XY:

196

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.000626

Gnomad4 AMR

AF:

0.00321

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00229

Gnomad4 FIN

AF:

0.000755

Gnomad4 NFE

AF:

0.00469

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00454

Hom.:

Bravo

AF:

0.00317

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00465

AC:

ExAC

AF:

0.00305

AC:

370

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00409

EpiControl

AF:

0.00486

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:23Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:8Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 21, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Sep 29, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 17, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 24, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 proband of European ancestry in homozygous state (Verlander 1994). Classified as Benign in ClinVar by GeneDx. MAF 0.4%. -

Fanconi anemia complementation group C

Uncertain:1Benign:4

May 29, 2019

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

May 18, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 25, 2017

Counsyl

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1Benign:4

Aug 26, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FANCC: BP4, BS2 -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 28, 2020

Leiden Open Variation Database

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: curation

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

Fanconi anemia

Benign:3

Jun 14, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 16, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Hereditary cancer-predisposing syndrome

Benign:2

Dec 03, 2015

Vantari Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 21, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Fanconi anemia complementation group A

Benign:1

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast

Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FANCC p.Asp195Val variant was identified in 2 of 436 proband chromosomes (frequency: 0.005) from individuals or families of northern or eastern European and southern Italian descent with pancreatic cancer and Fanconi Anemia (Verlander 1994, Van Der Heijden 2003). The variant was also identified in the following databases: dbSNP (ID: rs1800365), in the ClinVar database as benign by GeneDx, Emory Genetics, Invitae, Vantari Genetics; as likely benign by Centre for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, Prevention Genetics and Laboratory for Molecular Medicine, Partners Health Care Personalized Medicine; and as uncertain significance by Division of Genomic Diagnostics, Children's Hospital of Philadelphia Study Description: and in Clinvitae database as benign by Emyclass. The variant was also listed in the LOVD 3.0 database; however no relevant information was given. The variant was not identified in Cosmic and MutDB. In addition, the variant was identified in the 1000 Genomes Project in 13 of 5000 chromosomes (frequency: 0.003) and the NHLBI GO Exome Sequencing Project in 40 of 8600 European American and in 4 of 4406 African American alleles. The variant was identified in control databases in 842 (4 homozygous) of 277070 chromosomes at a frequency of 0.003 increasing the likelihood this could be a low frequency variant (Genome Aggregation Consortium Feb 27, 2017). Breakdown of observations by population is: European (Non-Finnish) in 568 (3 homozygous) of 126606 chromosomes (freq: 0.004), Ashkenazi Jewish in 36 of 10144 chromosomes (freq: 0.004), South Asian in 107 of 30766 chromosomes (freq: 0.003), Latino in 95 (1 homozygous) of 34412 chromosomes (freq: 0.003), Other in 16 of 6456 chromosomes (freq: 0.001), African in 12 of 24028 chromosomes (freq: 0.0005), and European (Finnish) in 8 of 25788 chromosomes (freq: 0.0003), while not observed in the East Asian population. The p.Asp195 residue is conserved in in mammals but not in more distantly related organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Asp195Val variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the Fanconi anaemia group C protein functional domain. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.51

D;D;T

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.89

.;D;D

MetaRNN

Benign

0.027

T;T;T

MetaSVM

Benign

-0.53

MutationAssessor

Uncertain

2.4

M;M;.

PrimateAI

Benign

0.38

PROVEAN

Pathogenic

-5.6

D;D;.

REVEL

Uncertain

0.42

Sift

Uncertain

0.0040

D;D;.

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

0.99

D;D;.

Vest4

0.83

MVP

0.87

MPC

0.40

ClinPred

0.028

GERP RS

4.8

Varity_R

0.45

gMVP

0.49

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

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