Submissions for variant NM_000136.3(FANCC):c.3G>A (p.Met1Ile)

dbSNP: rs1368374192

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000779587	SCV000916271	uncertain significance	Fanconi anemia complementation group C	2018-10-17	criteria provided, single submitter	clinical testing	The FANCC c.3G>A (p.Met1?) variant is predicted to disrupt the initiator codon, and may interfere with protein expression. The p.Met1? variant has not been reported in the literature in association with Fanconi anemia but was identified in an individual with head and neck squamous cell carcinoma (Chandrasekharappa et al. 2017). Control data are unavailable for this variant, which is reported at a frequency of 0.000009 in the European (non-Finnish) population of the Genome Aggregation Database. However, this frequency is based on one allele only, so the variant is presumed to be rare. Based on the variant frequency and the disease prevalence, penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Due to the potential impact on protein expression and the lack of clarifying evidence, the p.Met1? variant is classified as a variant of unknown significance but suspicious for pathogenicity for Fanconi anemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV001869147	SCV002201458	uncertain significance	Fanconi anemia	2021-07-01	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the FANCC mRNA. The next in-frame methionine is located at codon 16. This variant is not present in population databases (ExAC no frequency). Disruption of the initiator codon has been observed in individual(s) with head and neck cancer (PMID: 28678401). ClinVar contains an entry for this variant (Variation ID: 632544). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307613	SCV002600513	uncertain significance	not specified	2022-10-15	criteria provided, single submitter	clinical testing	Variant summary: FANCC c.3G>A (p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon; the next in-frame Methionine occurs at codon 16 in the native protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250170 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3G>A has been reported in the literature in at least one individual affected with Head and Neck Squamous Cell Carcinoma (Chandrasekharappa_2017). This report does not provide unequivocal conclusions about association of the variant with Fanconi Anemia Group C. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters have assessed the variant since 2014: both classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002352294	SCV002619600	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-07	criteria provided, single submitter	clinical testing	The p.M1? pathogenic mutation (also known as c.3G>A) is located in coding exon 1 of the FANCC gene and results from a G to A substitution at nucleotide position 3. This alters the methionine residue at the initiation codon (ATG). Sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.