rs143152201

chr9-95249263-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000136.3(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 NM_000136.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:2
• Conservation: PhyloP100: 2.31

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 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: {Uncertain_significance=7, Likely_benign=2}. Variant chr9-95249263-C-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152134 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.000634 AC XY: 86 AN XY: 135576

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.: 3 Cov.: 31 AF XY: 0.000476 AC XY: 346 AN XY: 727224

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: 31 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74430

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.: 0

Bravo AF: 0.000189

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000576 AC: 70

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign: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	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. -
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. -

Fanconi anemia complementation group C Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
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. -

Fanconi anemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

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. -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	22
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	D
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.018	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
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	T
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

Other links and lift over

dbSNP: rs143152201; hg19: chr9-98011545; COSMIC: COSV56658124;