rs143152201

Positions:

chr9-95249263-C-T

Variant summary

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

The ENST00000289081.8(FANCC):c.29G>A(p.Cys10Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000386 in 1,614,086 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. C10G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00040 ( 3 hom. )

Consequence

FANCC
ENST00000289081.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:3

Conservation

PhyloP100: 2.31

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:

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=0.017911524).

BP6

Variant 9-95249263-C-T is Benign according to our data. Variant chr9-95249263-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127538.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=6}. Variant chr9-95249263-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCC	NM_000136.3 linkuse as main transcript	c.29G>A	p.Cys10Tyr	missense_variant	2/15	ENST00000289081.8	NP_000127.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCC	ENST00000289081.8 linkuse as main transcript	c.29G>A	p.Cys10Tyr	missense_variant	2/15	1	NM_000136.3	ENSP00000289081	P1

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000498

AC:

125

AN:

250830

Hom.:

AF XY:

0.000634

AC XY:

AN XY:

135576

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.000398

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00150

Gnomad FIN exome

AF:

0.000509

Gnomad NFE exome

AF:

0.000495

Gnomad OTH exome

AF:

0.000817

GnomAD4 exome

AF:

0.000405

AC:

592

AN:

1461834

Hom.:

Cov.:

AF XY:

0.000476

AC XY:

346

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.000421

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00168

Gnomad4 FIN exome

AF:

0.000506

Gnomad4 NFE exome

AF:

0.000342

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.000204

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000348

Hom.:

Bravo

AF:

0.000189

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000576

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 24, 2020	This variant is associated with the following publications: (PMID: 28717660, 28767289, 26689913, 29021619) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 17, 2016	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 04, 2020	DNA sequence analysis of the FANCC gene demonstrated a sequence change, c.29G>A, in exon 2 that results in an amino acid change, p.Cys10Tyr. This sequence change has been described in the gnomAD database with a frequency of 0.15% in the South Asian sub-population (dbSNP rs143152201). The p.Cys10Tyr change has been reported in individuals with breast cancer, pancreatic cancer, low-grade glioma, and acute myeloid leukemia (PMID: 26689913; Lu 2015, Cabanillas 2017). The p.Cys10Tyr change affects a poorly conserved amino acid residue located in a domain of the FANCC protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Cys10Tyr substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Cys10Tyr change remains unknown at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 27, 2023	Variant summary: FANCC c.29G>A (p.Cys10Tyr) 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 0.0005 in 250830 control chromosomes, predominantly at a frequency of 0.0015 within the South Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in FANCC causing Fanconi Anemia Group C (0.0005 vs 0.0018), allowing no conclusion about variant significance. c.29G>A has been reported in the literature in individuals affected with pancreatic cancer, prostate cancer and other GI cancer, without strong evidence for causality (example, Bhai_2021, Shindo_2017) . In a large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 53/60466 cases and 46/53461 controls (Dorling_2021 through LOVD).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: 34326862, 28767289, 33471991). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (VUS=6, Likely benign=2). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Fanconi anemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 03, 2022

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 10 of the FANCC protein (p.Cys10Tyr). This variant is present in population databases (rs143152201, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 127538). 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. -

Fanconi anemia complementation group C

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The FANCC p.Cys10Tyr variant was identified in 1 of 72 proband chromosomes (frequency: 0.01) from individuals with a personal and/or family history of cancer (Cabanillas 2017). The variant was also identified in dbSNP (ID: rs143152201) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, GeneDx and three other submitters), and in LOVD 3.0. The variant was identified in control databases in 129 of 276522 chromosomes at a frequency of 0.0005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 4 of 6454 chromosomes (freq: 0.0006), Latino in 3 of 34402 chromosomes (freq: 0.00009), European in 59 of 126134 chromosomes (freq: 0.0005), Ashkenazi Jewish in 4 of 10132 chromosomes (freq: 0.0004), Finnish in 13 of 25776 chromosomes (freq: 0.0005), and South Asian in 46 of 30778 chromosomes (freq: 0.002), while the variant was not observed in the African or East Asian populations. The p.Cys10 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2020

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. -

Hereditary cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Sep 11, 2024

This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.088

T;T;T;.;T;.;.;.

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.74

.;T;T;T;T;T;T;T

M_CAP

Benign

0.0059

MetaRNN

Benign

0.018

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;N;.;.;.;.;.;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.83

N;N;.;.;N;.;.;.

REVEL

Benign

0.057

Sift

Benign

0.070

T;T;.;.;T;.;.;.

Sift4G

Benign

0.094

T;T;T;.;D;.;.;.

Polyphen

0.62

P;P;.;.;P;.;.;.

Vest4

0.11

MVP

0.66

MPC

0.17

ClinPred

0.022

GERP RS

2.3

Varity_R

0.071

gMVP

0.22

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