rs587779904

chr9-95172132-TATGAGA-TT

Variant summary

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

The NM_000136.3(FANCC):c.355_360delinsA(p.Ser119AsnfsTer8) variant causes a frameshift 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: Genomes: not found (cov: 32)
• Consequence: FANCC NM_000136.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 3.22

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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-95172133-ATGAGA-T is Pathogenic according to our data. Variant chr9-95172133-ATGAGA-T is described in ClinVar as [Pathogenic]. Clinvar id is 127540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCC	NM_000136.3	c.355_360delinsA	p.Ser119AsnfsTer8	frameshift_variant	5/15	ENST00000289081.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCC	ENST00000289081.8	c.355_360delinsA	p.Ser119AsnfsTer8	frameshift_variant	5/15	1	NM_000136.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group C Pathogenic:5

Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	Feb 28, 2020	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 09, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 14, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Aug 21, 2023	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. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 19, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 2022	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) -

Fanconi anemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 23, 2022

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 and 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

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 26, 2023

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 that results in the same frameshift and premature protein truncation, was observed in the homozygous state in a patient with Fanconi anemia (Ameziane. 2008. PubMed ID: 17924555). This variant is not present in a large population database (http://gnomad.broadinstitute.org). 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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 19, 2024

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: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587779904; hg19: chr9-97934415;