9-95172098-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_000136.3(FANCC):c.395C>G(p.Ala132Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,613,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 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. A132T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

FANCC
NM_000136.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: -0.475

Publications

3 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 Gene-Disease associations (from GenCC):

Fanconi anemia complementation group C
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
colorectal cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
malignant pancreatic neoplasm
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
ovarian cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
prostate cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
breast cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

FANCC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02167347).

BP6

Variant 9-95172098-G-C is Benign according to our data. Variant chr9-95172098-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127541. Variant chr9-95172098-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127541. Variant chr9-95172098-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127541. Variant chr9-95172098-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127541. Variant chr9-95172098-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127541. Variant chr9-95172098-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127541. Variant chr9-95172098-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127541. Variant chr9-95172098-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127541. Variant chr9-95172098-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127541. Variant chr9-95172098-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127541. Variant chr9-95172098-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127541. Variant chr9-95172098-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127541. Variant chr9-95172098-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127541. Variant chr9-95172098-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 127541.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCC	NM_000136.3 link	c.395C>G	p.Ala132Gly	missense_variant	Exon 5 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.395C>G	p.Ala132Gly	missense_variant	Exon 5 of 15	1	NM_000136.3	ENSP00000289081.3		Q00597

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152160

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000318

AC:

AN:

251186

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000246

AC:

AN:

1461038

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

726880

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33444

American (AMR)

AF:

0.0000671

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39614

South Asian (SAS)

AF:

0.00

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000252

AC:

AN:

1111380

Other (OTH)

AF:

0.0000663

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.439

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:

0.0000460

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41422

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

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:

0.000141

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Sep 11, 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: FANCC c.395C>G (p.Ala132Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251186 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.395C>G has been reported in the literature in individuals affected with Breast Cancer or undertaking multiple gene panel testing, without strong evidence of causality (example, Guindalini_2022, Lu_2015). It is also present in both breast cancer cases and controls in a large study by the Breast Cancer Association Consortium (Dorling_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Fanconi Anemia Group C. 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: 35264596, 26689913, 33471991). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=6, Likely benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Apr 16, 2021

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change does not appear to have been previously described in patients with FANCC-related disorders and has been described in the gnomAD database with a low population frequency of 0.0032% (dbSNP rs587779905). The p.Ala132Gly change affects a poorly conserved amino acid residue located in a domain of the FANCC protein that is known to be functional. The p.Ala132Gly substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ala132Gly change remains unknown at this time. -

Fanconi anemia

Uncertain:1

Oct 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 132 of the FANCC protein (p.Ala132Gly). This variant is present in population databases (rs587779905, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with FANCC-related conditions. ClinVar contains an entry for this variant (Variation ID: 127541). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FANCC protein function. 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. -

not provided

Uncertain:1

May 30, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 35264596, 26689913, Gordon2000[Book], 33471991) -

Fanconi anemia complementation group C

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Hereditary cancer

Benign:1

Jan 23, 2024

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Nov 28, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.71

CADD

Benign

4.0

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.047

T;T;T;.;T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0027

LIST_S2

Benign

0.56

.;T;T;T;T;T

M_CAP

Benign

0.0016

MetaRNN

Benign

0.022

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.8

N;N;.;.;.;.

PhyloP100

-0.47

PrimateAI

Benign

0.22

PROVEAN

Benign

0.92

N;N;.;.;N;.

REVEL

Benign

0.032

Sift

Benign

0.44

T;T;.;.;T;.

Sift4G

Benign

0.84

T;T;T;.;T;.

Polyphen

0.0

B;B;.;.;B;.

Vest4

0.078

MutPred

0.40

Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);Loss of helix (P = 0.0093);

MVP

0.40

MPC

0.053

ClinPred

0.034

GERP RS

-3.9

Varity_R

0.028

gMVP

0.10

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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