rs1800360

chr9-95172085-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000136.3(FANCC):c.408A>G(p.Gln136=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00392 in 1,613,334 control chromosomes in the GnomAD database, including 232 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (121 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (111 hom.)
• Consequence: FANCC NM_000136.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:12
• Conservation: PhyloP100: -0.324

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 9-95172085-T-C is Benign according to our data. Variant chr9-95172085-T-C is described in ClinVar as [Benign]. Clinvar id is 255275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95172085-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.324 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0742 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCC	NM_000136.3	c.408A>G	p.Gln136=	synonymous_variant	5/15	ENST00000289081.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCC	ENST00000289081.8	c.408A>G	p.Gln136=	synonymous_variant	5/15	1	NM_000136.3	P1

Frequencies

GnomAD3 genomes AF: 0.0218 AC: 3320 AN: 152134 Hom.: 121 Cov.: 32

Gnomad AFR AF: 0.0766

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0162

GnomAD3 exomes AF: 0.00545 AC: 1370 AN: 251184 Hom.: 61 AF XY: 0.00375 AC XY: 509 AN XY: 135776

Gnomad AFR exome AF: 0.0772

Gnomad AMR exome AF: 0.00269

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00206 AC: 3003 AN: 1461082 Hom.: 111 Cov.: 29 AF XY: 0.00176 AC XY: 1277 AN XY: 726914

Gnomad4 AFR exome AF: 0.0759

Gnomad4 AMR exome AF: 0.00320

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000351

Gnomad4 OTH exome AF: 0.00419

GnomAD4 genome AF: 0.0218 AC: 3320 AN: 152252 Hom.: 121 Cov.: 32 AF XY: 0.0206 AC XY: 1532 AN XY: 74456

Gnomad4 AFR AF: 0.0764

Gnomad4 AMR AF: 0.00660

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.00653 Hom.: 42

Bravo AF: 0.0249

Asia WGS AF: 0.00433 AC: 16 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 29, 2016	Variant summary: The FANCC c.408A>G variant affects a non-conserved nucleotide, resulting in a synonymous change. Mutation Taster predicts a benign outcome for this variant, and 5/5 Alamut algorithms predict no significant change to splicing. This variant was found in 807/120880 control chromosomes (36 homozygotes) at a frequency of 0.006676, which is about 4 times the maximal expected frequency of a pathogenic FANCC allele (0.0017678), suggesting this variant is benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant was classified as benign. -
Uncertain significance, no assertion criteria provided	curation	Leiden Open Variation Database	Feb 28, 2020	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 20, 2021	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Fanconi anemia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 10, 2017	- -

Fanconi anemia complementation group C Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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The FANCC p.Gln136= variant was identified in dbSNP (ID: rs1800360) as “With other allele” and in control databases in 2016 (87 homozygous) of 276974 chromosomes at a frequency of 0.007 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1891 (87 homozygous) of 24020 chromosomes (freq: 0.08), Other in 17 of 6456 chromosomes (freq: 0.003), Latino in 94 of 34404 chromosomes (freq: 0.003), European Non-Finnish in 11 of 126548 chromosomes (freq: 0.00009), and South Asian in 3 of 30774 chromosomes (freq: 0.0001), while the variant was not observed in the Ashkenazi Jewish, East Asian, and European Finnish populations. The p.Gln136= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 29, 2016

This alteration is classified as 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
BayesDel_noAF	Benign	-0.90
Cadd	Benign	3.4
Dann	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1800360; hg19: chr9-97934367;