Submissions for variant NM_000136.3(FANCC):c.767A>G (p.His256Arg)

gnomAD frequency: 0.00006  dbSNP: rs730881716

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000513268	SCV000211042	uncertain significance	not provided	2023-09-13	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32546565, 15695377, 26362256, 26689913, 28767289, 29719599, 32659497, Gordon2000[Book])
Invitae	RCV000205450	SCV000260164	uncertain significance	Fanconi anemia	2022-09-30	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 256 of the FANCC protein (p.His256Arg). This variant is present in population databases (rs730881716, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with FANCC-related conditions. ClinVar contains an entry for this variant (Variation ID: 182476). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FANCC protein function. 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.
CeGaT Center for Human Genetics Tuebingen	RCV000513268	SCV000609343	uncertain significance	not provided	2017-06-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000571601	SCV000673323	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-09	criteria provided, single submitter	clinical testing	The p.H256R variant (also known as c.767A>G), located in coding exon 7 of the FANCC gene, results from an A to G substitution at nucleotide position 767. The histidine at codon 256 is replaced by arginine, an amino acid with highly similar properties. In one study, this alteration was detected in 2/6385 invasive epithelial ovarian cancer patients and 5/6115 controls of broad European ancestry (Song H et al. J Med Genet, 2021 05;58:305-313). In another study, this alteration was identified in 0/421 pancreatic cancer cases and 1/654 controls (Couch FJ et al. Cancer Res. 2005 Jan;65:383-6). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000513268	SCV002010150	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001276590	SCV002814390	uncertain significance	Fanconi anemia complementation group C	2021-08-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488408	SCV004241234	uncertain significance	not specified	2023-12-18	criteria provided, single submitter	clinical testing	Variant summary: FANCC c.767A>G (p.His256Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 251426 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FANCC causing Fanconi Anemia Group C (6.8e-05 vs 0.0018), allowing no conclusion about variant significance. c.767A>G has been reported in the literature in an individual affected with pancreatic cancer along with a potentially causitive variant (Shindo_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. The following publications have been ascertained in the context of this evaluation (PMID: 15695377, 28767289). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Leiden Open Variation Database	RCV000513268	SCV001365322	uncertain significance	not provided	2020-02-28	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.
Natera, Inc.	RCV001276590	SCV001463017	uncertain significance	Fanconi anemia complementation group C	2018-10-02	no assertion criteria provided	clinical testing