rs763151358

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP5

The NM_021922.3(FANCE):c.598C>T(p.Arg200Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000527 in 1,613,906 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R200H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

FANCE
NM_021922.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3

Conservation

PhyloP100: 1.65

Publications

8 publications found

Variant links:

Genes affected

FANCE (HGNC:3586): (FA complementation group E) 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 E. [provided by RefSeq, Jul 2008]

FANCE Gene-Disease associations (from GenCC):

Fanconi anemia complementation group E
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

FANCE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP5

Variant 6-35456096-C-T is Pathogenic according to our data. Variant chr6-35456096-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 221623.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCE	NM_021922.3 link	c.598C>T	p.Arg200Cys	missense_variant	Exon 2 of 10	ENST00000229769.3	NP_068741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCE	ENST00000229769.3 link	c.598C>T	p.Arg200Cys	missense_variant	Exon 2 of 10	1	NM_021922.3	ENSP00000229769.2

Frequencies

GnomAD3 genomes

AF:

0.0000724

AC:

AN:

152022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000580

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:

0.0000598

AC:

AN:

250994

AF XY:

0.0000663

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000381

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000506

AC:

AN:

1461766

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

727166

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000353

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53340

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000459

AC:

AN:

1111982

Other (OTH)

AF:

0.0000662

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

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:

0.0000723

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41494

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000581

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.530

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:

0.0000712

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Fanconi anemia complementation group E

Uncertain:2

Jul 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 200 of the FANCE protein (p.Arg200Cys). This variant is present in population databases (rs763151358, gnomAD 0.04%). This missense change has been observed in individual(s) with colorectal cancer and breast cancer (PMID: 27165003). ClinVar contains an entry for this variant (Variation ID: 221623). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Feb 28, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Carcinoma of colon

Pathogenic:1

Nov 01, 2015

Genetic Predisposition to Colorectal Cancer Group, Institut d’Investigacions Biomediques August Pi i Sunyer

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant detected by whole exome sequencing in a family presenting aggregation mainly for colorectal cancer but also for breast cancer -

not specified

Uncertain:1

Dec 13, 2023

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: FANCE c.598C>T (p.Arg200Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 250994 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FANCE causing Fanconi Anemia (6e-05 vs 0.00048), allowing no conclusion about variant significance. c.598C>T has been reported in the literature in individuals affected with Colon cancer, Breast cancer and other unspecified childhood cancer, without strong evidence for causality (example, Esteban-Jurado_2016, Sylvester_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Fanconi Anemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27165003, 34687117). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.31

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.51

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.084

MetaRNN

Uncertain

0.64

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.9

PhyloP100

1.7

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.5

REVEL

Benign

0.15

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.80

MutPred

0.35

Loss of solvent accessibility (P = 0.0561);

MVP

0.67

MPC

0.58

ClinPred

0.83

GERP RS

4.5

Varity_R

0.25

gMVP

0.26

Mutation Taster

=82/18

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