Submissions for variant NM_000136.3(FANCC):c.37C>T (p.Gln13Ter)

gnomAD frequency: 0.00001  dbSNP: rs121917784

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115351	SCV000149260	pathogenic	not provided	2023-04-27	criteria provided, single submitter	clinical testing	Nonsense 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; Not observed at significant frequency in large population cohorts (gnomAD); Observed in the heterozygous state in individuals with breast and other cancers referred for genetic testing at GeneDx; This variant is associated with the following publications: (PMID: 17384215, 8103176, 8844212, 24584348, 26596371, 12552564, 8128956, 29922827, 26740942, 12670332, 20869034, 12393516, 10666230, 15516848, 9207444, 26681312, 8639804, 31937788, 29625052, 31589614)
Counsyl	RCV000012826	SCV000220353	likely pathogenic	Fanconi anemia complementation group C	2014-05-27	criteria provided, single submitter	literature only
Invitae	RCV000476519	SCV000549951	pathogenic	Fanconi anemia	2023-08-24	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 12046). This variant is also known as c.292C>T. This premature translational stop signal has been observed in individual(s) with Fanconi anemia (PMID: 8103176, 8128956, 9207444, 26740942). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs121917784, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Gln13*) 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000012826	SCV000917333	pathogenic	Fanconi anemia complementation group C	2018-02-15	criteria provided, single submitter	clinical testing	Variant summary: FANCC c.37C>T (p.Gln13X) 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 (eg. c.65G>A, p.Trp22X; c.553C>T, p.Arg185X; c.1642C>T, p.Arg548X). The variant allele was found at a frequency of 8.1e-06 in 245648 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in FANCC causing Fanconi Anemia Group C (8.1e-06 vs 1.80E-03), allowing no conclusion about variant significance. c.37C>T has been reported in the literature in multiple individuals affected with Fanconi Anemia Group C (De Rocco_2014, Gillio_1997, Susswein_2015). 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000012826	SCV001163262	pathogenic	Fanconi anemia complementation group C		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001021181	SCV001182762	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-12	criteria provided, single submitter	clinical testing	The p.Q13* pathogenic mutation (also known as c.37C>T), located in coding exon 1 of the FANCC gene, results from a C to T substitution at nucleotide position 37. This changes the amino acid from a glutamine to a stop codon within coding exon 1. This alteration has been reported in the homozygous and compound heterozygous state in multiple individuals with a clinical diagnosis of Fanconi anemia (Verlander PC et al. Am. J. Hum. Genet., 1994 Apr;54:595-601; Murer-Orlando M et al. Lancet, 1993 Sep;342:686; Gillio AP et al. Blood, 1997 Jul;90:105-10; Nicchia E et al. Mol Genet Genomic Med, 2015 Nov;3:500-12). In addition to the information presented in the literature, 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.
Revvity Omics, Revvity	RCV000012826	SCV002022334	pathogenic	Fanconi anemia complementation group C	2019-05-21	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000012826	SCV002798734	pathogenic	Fanconi anemia complementation group C	2021-07-06	criteria provided, single submitter	clinical testing
OMIM	RCV000012826	SCV000033066	pathogenic	Fanconi anemia complementation group C	1993-09-11	no assertion criteria provided	literature only
GeneReviews	RCV000012826	SCV000057807	not provided	Fanconi anemia complementation group C		no assertion provided	literature only	Common in northern Europeans
Leiden Open Variation Database	RCV000012826	SCV001365306	pathogenic	Fanconi anemia complementation group C	2020-02-28	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.
Natera, Inc.	RCV000476519	SCV002081319	pathogenic	Fanconi anemia	2017-03-17	no assertion criteria provided	clinical testing