rs730881710

Variant names:

• chr9-95107210-TGA-T
• rs730881710
• NM_000136.3:c.1387_1388delTC

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000136.3(FANCC):​c.1387_1388delTC​(p.Ala464ProfsTer53) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000205 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FANCC NM_000136.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 5.39

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]

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]

LOC107987102 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-95107210-TGA-T is Pathogenic according to our data. Variant chr9-95107210-TGA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 182468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCC	NM_000136.3	c.1387_1388delTC	p.Ala464ProfsTer53	frameshift_variant	Exon 14 of 15	ENST00000289081.8	NP_000127.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCC	ENST00000289081.8	c.1387_1388delTC	p.Ala464ProfsTer53	frameshift_variant	Exon 14 of 15	1	NM_000136.3	ENSP00000289081.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251224 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135812

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461858 Hom.: 0 AF XY: 0.00000275 AC XY: 2 AN XY: 727222

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group C Pathogenic:3

Jan 19, 2018

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 29, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia Pathogenic:1

Feb 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ala464Profs*53) in the FANCC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 95 amino acid(s) of the FANCC protein. This variant is present in population databases (rs730881710, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 182468). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts a region of the FANCC protein in which other variant(s) (p.Arg548*) have been determined to be pathogenic (PMID: 8103176, 8844212, 24584348). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

FANCC-related disorder Pathogenic:1

Sep 12, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FANCC c.1387_1388delTC variant is predicted to result in a frameshift and premature protein termination (p.Ala464Profs*53). This variant has been reported in an individual with breast cancer (Table S1, Susswein et al. 2016. PubMed ID: 26681312). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been reported in control populations (eTable 3, Hu et al. 2018. PubMed ID: 29922827). It is reported as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/182468/). Frameshift variants in FANCC are expected to be pathogenic. This variant is interpreted as pathogenic. -

not provided Pathogenic:1

Sep 08, 2014

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This deletion of 2 nucleotides in FANCC is denoted c.1387_1388delTC at the cDNA level and p.Ala464ProfsX53 (A464PfsX53) at the protein level. The normal sequence, with the bases that are deleted in brackets, is CCTC[TC]AGCC. The deletion causes a frameshift, which changes an Alanine to a Proline at codon 464, and creates a premature stop codon at position 53 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. we consider this variant to be pathogenic.FANCC has been only recently described in association with cancer predisposition and the risks are not well understood. Based on available data, the presence of a FANCC mutation may confer an increased risk for female breast cancer (Thompson 2012, Berwick 2007). Berwick et al. (2007) identified 33 female FANCC mutation carriers; all grandmothers of known Fanconi Anemia patients. In this group of women the observed cases of breast cancer (n=6) was significantly higher than the expected cases of breast cancer (SIR = 2.4). Thompson et al. (2012) studied 438 BRCA-negative breast cancer families and identified 3 families with deleterious FANCC mutations. In two of these families, the identified truncating FANCC mutations were found in multiple affected family members. The authors conclude that the co-segregation of FANCC mutations in these families appears to be consistent with moderately penetrant breast cancer alleles. Fanconi Anemia (FA) is a rare autosomal recessive condition that can be caused by two mutations (one affecting each allele) in the FANCC gene. This condition is characterized by an increased risk for childhood malignancy including leukemia and solid tumors, as well as distinctive physical abnormalities and bone marrow failure. If a FANCC mutation carrier'spartner is also a carrier for a FANCC mutation, the risk to have a child with FA is 25% with each pregnancy. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jan 04, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1387_1388delTC pathogenic mutation, located in coding exon 13 of the FANCC gene, results from a deletion of two nucleotides at nucleotide positions 1387 to 1388, causing a translational frameshift with a predicted alternate stop codon (p.A464Pfs*53). 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)		0.0		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: rs730881710; hg19: chr9-97869492;