Submissions for variant NM_000136.3(FANCC):c.996+1G>A

dbSNP: rs370510954

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000671064	SCV000796004	likely pathogenic	Fanconi anemia complementation group C	2017-11-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000671064	SCV000917337	likely pathogenic	Fanconi anemia complementation group C	2018-07-02	criteria provided, single submitter	clinical testing	Variant summary: FANCC c.996+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 121274 control chromosomes (ExAC). To our knowledge, no occurrence of c.996+1G>A in individuals affected with Fanconi Anemia Group C and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV002532107	SCV003299625	likely pathogenic	Fanconi anemia	2022-06-29	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 555274). This variant has not been reported in the literature in individuals affected with FANCC-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 10 of the FANCC gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FANCC are known to be pathogenic (PMID: 17924555).
Ambry Genetics	RCV003303098	SCV003998863	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-03-22	criteria provided, single submitter	clinical testing	The c.996+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 9 of the FANCC gene. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Leiden Open Variation Database	RCV000671064	SCV001365328	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.	RCV000671064	SCV001457659	likely pathogenic	Fanconi anemia complementation group C	2020-09-16	no assertion criteria provided	clinical testing