rs1268491295

Positions:

• chr9-95249286-A-AG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000289081.8(FANCC):​c.5_6insC​(p.Gln3SerfsTer9) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A2A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FANCC ENST00000289081.8 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.01

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 154 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-95249286-A-AG is Pathogenic according to our data. Variant chr9-95249286-A-AG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 558692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCC	NM_000136.3	c.5_6insC	p.Gln3SerfsTer9	frameshift_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.5_6insC	p.Gln3SerfsTer9	frameshift_variant	2/15	1	NM_000136.3	ENSP00000289081	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group C Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 05, 2018	- -

Fanconi anemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2020

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in FANCC are known to be pathogenic (PMID: 17924555). This variant has not been reported in the literature in individuals with FANCC-related conditions. ClinVar contains an entry for this variant (Variation ID: 558692). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln3Serfs*9) in the FANCC gene. It is expected to result in an absent or disrupted protein product. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 29, 2024

The c.5dupC pathogenic mutation, located in coding exon 1 of the FANCC gene, results from a duplication of C at nucleotide position 5, causing a translational frameshift with a predicted alternate stop codon (p.Q3Sfs*9). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1268491295; hg19: chr9-98011568;