rs1800361

Positions:

• chr9-95249215-G-A
• chr9-95249215-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000136.3(FANCC):​c.77C>T​(p.Ser26Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00579 in 1,614,112 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0050 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0059 (29 hom.)
• Consequence: FANCC NM_000136.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:20 O:1
• Conservation: PhyloP100: 3.98

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010334253).
• BP6: Variant 9-95249215-G-A is Benign according to our data. Variant chr9-95249215-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134301.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, not_provided=1, Benign=9, Uncertain_significance=2}. Variant chr9-95249215-G-A is described in Lovd as [Benign]. Variant chr9-95249215-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00587 (8584/1461840) while in subpopulation MID AF= 0.0231 (133/5768). AF 95% confidence interval is 0.0199. There are 29 homozygotes in gnomad4_exome. There are 4198 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCC	NM_000136.3	c.77C>T	p.Ser26Phe	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	c.77C>T	p.Ser26Phe	missense_variant	2/15	1	NM_000136.3	ENSP00000289081	P1

Frequencies

GnomAD3 genomes AF: 0.00502 AC: 764 AN: 152154 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00759

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00603

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00713

Gnomad OTH AF: 0.0101

GnomAD3 exomes AF: 0.00486 AC: 1220 AN: 251236 Hom.: 5 AF XY: 0.00465 AC XY: 631 AN XY: 135762

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00408

Gnomad ASJ exome AF: 0.00894

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00199

Gnomad FIN exome AF: 0.00564

Gnomad NFE exome AF: 0.00668

Gnomad OTH exome AF: 0.00587

GnomAD4 exome AF: 0.00587 AC: 8584 AN: 1461840 Hom.: 29 Cov.: 31 AF XY: 0.00577 AC XY: 4198 AN XY: 727228

Gnomad4 AFR exome AF: 0.00167

Gnomad4 AMR exome AF: 0.00367

Gnomad4 ASJ exome AF: 0.00899

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00185

Gnomad4 FIN exome AF: 0.00509

Gnomad4 NFE exome AF: 0.00648

Gnomad4 OTH exome AF: 0.00594

GnomAD4 genome AF: 0.00502 AC: 764 AN: 152272 Hom.: 6 Cov.: 32 AF XY: 0.00506 AC XY: 377 AN XY: 74454

Gnomad4 AFR AF: 0.000963

Gnomad4 AMR AF: 0.00758

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00603

Gnomad4 NFE AF: 0.00713

Gnomad4 OTH AF: 0.00995

Alfa AF: 0.00671 Hom.: 8

Bravo AF: 0.00443

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00686 AC: 59

ExAC AF: 0.00465 AC: 565

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00698

EpiControl AF: 0.00842

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:20 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:7 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 29, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 02, 2021	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 08, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 05, 2018	Variant summary: FANCC c.77C>T (p.Ser26Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0049 in 276964 control chromosomes in the gnomAD database, including 8 homozygotes. The observed variant frequency is approximately 3-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in FANCC causing Fanconi Anemia Group C phenotype (0.0018), strongly suggesting that the variant is benign. The variant, c.77C>T, was observed in a family, which did not segregate with disease (affected sibling lacking the variant (Verlander_1994).To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Oct 11, 2015	- -

not provided Uncertain:1 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 02, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	FANCC: BP4, BS2 -
Uncertain significance, flagged submission	curation	Leiden Open Variation Database	Feb 28, 2020	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Fanconi anemia complementation group C Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Fanconi anemia Benign:3

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 21, 2018	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Apr 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

FANCC-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 03, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Fanconi anemia complementation group A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The FANCC p.Ser26Phe variant was identified in 15 of 1470 proband chromosomes (frequency: 0.01) from British and American individuals or families with BRCA1/2 negative breast cancer, pancreatic cancer or leukemias (AML and ALL) and was present in 10 of 2270 control chromosomes (frequency: 0.004) from healthy individuals (Seal 2003, Barber 2003, Couch 2005, Rogers 2004). The variant did not cosegregate with disease in family members with pancreatic cancer, lymphoma or breast cancer in one study (Rogers 2004); was observed 4X greater in sporadic childhood AML patients vs those with ALL in another study (Barber 2003). The variant was also identified in dbSNP (ID: rs1800361) “With other allele”, ClinVar (classified as benign by GeneDx, EGL Genetic Diagnostics(Eurfins Clinical Diagnostics), Invitae, Div. of Genomic Diagnostics (Children's Hospital of Philadelphia); likely benign by Prevention Genetics and classification not provided by ITMI ), Clinvitae (3x), LOVD 3.0 (1x), and was not identified in Cosmic, and MutDB databases. The variant was identified in control databases in 1365 (8 homozygous) of 276964 chromosomes at a frequency of 0.005 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017), being identified in the following populations: African in 22 (1 homozygous) of 24038 chromosomes (frequency: 0009), Other in 41 of 6462 chromosomes (frequency: 006), Latino in 143 of 34416 chromosomes (frequency: 004), European Non-Finnish in 873 (5 homozygous) of 126482 chromosomes (frequency: 007), Ashkenazi Jewish in 91 of 10144 chromosomes (frequency: 009), European Finnish in 134 (2 homozygous) of 25784 chromosomes (frequency: 005), South Asian in 61 of 30780 chromosomes (frequency: 002), The variant was also identified by our laboratory in 1 individual with breast cancer, co-occurring with a pathogenic BRCA2 mutation (c.8195T>A, p.2732X). The p.Ser26 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Phe variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 31, 2018

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	0.23
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;T;T;.;T;.;.;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.88	.;D;D;D;D;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.010	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.9	M;M;.;.;.;.;.;.
MutationTaster	Benign	0.85	D;D
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.5	D;D;.;.;D;.;.;.
REVEL	Benign	0.23
Sift	Uncertain	0.0040	D;D;.;.;D;.;.;.
Sift4G	Uncertain	0.010	D;D;D;.;D;.;.;.
Polyphen		1.0	D;D;.;.;D;.;.;.
Vest4		0.26
MVP		0.87
MPC		0.36
ClinPred		0.011	T
GERP RS		4.2
Varity_R		0.20
gMVP		0.23

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: rs1800361; hg19: chr9-98011497; COSMIC: COSV104610575;