rs587779904
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000136.3(FANCC):c.355_360delTCTCATinsA(p.Ser119AsnfsTer8) variant causes a frameshift, missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000136.3 frameshift, missense
Scores
Clinical Significance
Conservation
Publications
- Fanconi anemia complementation group CInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health
- Fanconi anemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- colorectal cancerInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
- malignant pancreatic neoplasmInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
- ovarian cancerInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
- prostate cancerInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
- breast cancerInheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| FANCC | NM_000136.3 | c.355_360delTCTCATinsA | p.Ser119AsnfsTer8 | frameshift_variant, missense_variant | Exon 5 of 15 | ENST00000289081.8 | NP_000127.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| FANCC | ENST00000289081.8 | c.355_360delTCTCATinsA | p.Ser119AsnfsTer8 | frameshift_variant, missense_variant | Exon 5 of 15 | 1 | NM_000136.3 | ENSP00000289081.3 |
Frequencies
GnomAD3 genomes
GnomAD4 genome
ClinVar
Submissions by phenotype
Fanconi anemia complementation group C Pathogenic:6
Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -
Variant summary: FANCC c.355_360delinsA (p.Ser119AsnfsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 282396 control chromosomes. c.355_360delinsA has been reported in the literature in individuals affected with breast cancer (example, Susswein_2015, Frey_2017) and ovarian cancer (Carter_2018). A similar variant has also been reported as a homozygous genotype in an individual affected with Fanconi Anemia Group C (reported as c.356_360del, p.Ser119Tyrfs*8, Ameziane_2007). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Some submitters cite overlapping evidence utilized in the context of this evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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The FANCC c.355_360delinsA (p.Ser119AsnfsTer8) change causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay. This variant is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). Although this variant has not been reported in the literature in individuals with Fanconi anemia, downstream truncating variants have been identified in individuals with Fanconi anemia (PMID: 7689011, 16429406, 32487094). In summary, this variant meets criteria to be classified as pathogenic. -
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not provided Pathogenic:2
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in several probands with a personal and/or family history of breast and/or ovarian cancer (Frey 2017, Carter 2018, Palmer 2020); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 7689011, 28495237, 30322717, 26681312, 23028338, 32227564, 32427313) -
This frameshift variant alters the translational reading frame of the FANCC mRNA and causes the premature termination of FANCC protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with breast cancer (PMID: 32427313 (2020), 28495237 (2017), 26681312 (2015)) and ovarian cancer (PMID: 30322717 (2018)). It has also been reported in unaffected individuals (PMID: 32427313 (2020)). Based on the available information, this variant is classified as pathogenic. -
Fanconi anemia Pathogenic:1
This sequence change creates a premature translational stop signal (p.Ser119Asnfs*8) in the FANCC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FANCC are known to be pathogenic (PMID: 17924555). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast or ovarian cancer (PMID: 26681312, 30322717). ClinVar contains an entry for this variant (Variation ID: 417933). For these reasons, this variant has been classified as Pathogenic. -
FANCC-related disorder Pathogenic:1
The FANCC c.355_360delinsA variant is predicted to result in a frameshift and premature protein termination (p.Ser119Asnfs*8). This variant has been observed in at least three patients with breast cancer (Susswein et al. 2016. PubMed ID: 26681312). A similar variant defined as c.356_360delCTCAT, which results in the same frameshift and premature protein truncation, was observed in the homozygous state in a patient with Fanconi anemia (Ameziane et al. 2008. PubMed ID: 17924555). This variant is not present in a large population database, indicating it is rare. This variant is classified as pathogenic by a number of laboratories in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/127540/). Variants in FANCC resulting in premature protein termination and loss of function are known causes of FANCC-related disease and we categorize this variant as pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The c.355_360delTCTCATinsA pathogenic mutation, located in coding exon 4 of the FANCC gene, results from the deletion of 6 nucleotides and insertion of one nucleotide causing a translational frameshift with a predicted alternate stop codon (p.S119Nfs*8). Multiple studies have reported this variant in patients with a personal and/or family history of breast cancer (Thompson ER et al. PLoS Genet, 2012 Sep;8:e1002894; Susswein LR et al. Genet Med, 2016 08;18:823-32; Frey MK et al. Gynecol Oncol, 2017 07;146:123-128; Palmer JR et al. J Natl Cancer Inst, 2020 Dec;112:1213-1221). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at