rs730881717

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000136.3(FANCC):c.792T>G(p.Ser264Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S264G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

FANCC
NM_000136.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 0.121

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12888384).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCC	NM_000136.3 linkuse as main transcript	c.792T>G	p.Ser264Arg	missense_variant	8/15	ENST00000289081.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCC	ENST00000289081.8 linkuse as main transcript	c.792T>G	p.Ser264Arg	missense_variant	8/15	1	NM_000136.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152162

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251446

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000791

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000294

AC:

AN:

1461764

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727178

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000369

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000847

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 08, 2021	Variant summary: FANCC c.792T>G (p.Ser264Arg) 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 3.6e-05 in 251446 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.792T>G has been reported in the literature in an individual affected with childhood T-cell acute lymphoblastic leukemia (Burns_2018, Pouliot_2019) and in a prostate cancer tumor sample (Mateo_2020), however it is unclear whether the variant was somatic or germline occurrence in these cases. In a large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC) the variant was reported in 4/60466 cases and 8/53461 controls (Dorling_2021 through LOVD). These reports do not provide unequivocal conclusions about association of the variant with Fanconi Anemia Group C. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated a hypomorphic effect (about 75-80% of the wild-type function) based on viability, ability to rescue G2/M arrest, and efficiency in reducing radial chromosome formation after treatment with DNA cross-linking agents (Pouliot_2019). Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as uncertain significance. 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	May 01, 2020	DNA sequence analysis of the FANCC gene demonstrated a sequence change, c.792T>G, in exon 8 that results in an amino acid change, p.Ser264Arg. 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 0.0079% in the non-Finnish European subpopulations (dbSNP rs730881717). The p.Ser264Arg change affects a moderately conserved amino acid residue located in a domain of the FANCC protein that is known to be functional. The p.Ser264Arg 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.Ser264Arg change remains unknown at this time. -

Fanconi anemia

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 19, 2022	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 264 of the FANCC protein (p.Ser264Arg). This variant is present in population databases (rs730881717, gnomAD 0.008%). 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: 182477). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on FANCC function (PMID: 31721781). 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

Fulgent Genetics, Fulgent Genetics

Jul 30, 2021

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 09, 2019

Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 30404791) -

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.Ser264Arg variant was identified in 1 of 218 proband chromosomes (frequency: 0.005) from T-cell acute lymphoblastic leukemia clinical samples (Burns 2018). The variant was identified in dbSNP (rs730881717) as â€šÃ„Ãºwith uncertain significance alleleâ€šÃ„Ã¹ and ClinVar (classified as uncertain significance by Invitae, GeneDx and Integrated Genetics). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 9 of 251,446 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 9 of 113,742 chromosomes (freq: 0.00008); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, Finnish, Other or South Asian populations. The p.Ser264 residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out 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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 03, 2022

The p.S264R variant (also known as c.792T>G), located in coding exon 7 of the FANCC gene, results from a T to G substitution at nucleotide position 792. The serine at codon 264 is replaced by arginine, an amino acid with dissimilar properties. This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.62

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.092

T;T;T

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.056

M_CAP

Benign

0.0039

MetaRNN

Benign

0.13

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.97

L;L;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.38

N;N;.

REVEL

Benign

0.086

Sift

Benign

0.45

T;T;.

Sift4G

Benign

0.41

T;T;T

Polyphen

0.012

B;B;.

Vest4

0.26

MutPred

0.61

Gain of MoRF binding (P = 0.0246);Gain of MoRF binding (P = 0.0246);Gain of MoRF binding (P = 0.0246);

MVP

0.63

MPC

0.062

ClinPred

0.031

GERP RS

-3.4

Varity_R

0.058

gMVP

0.15

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