Submissions for variant NM_000136.3(FANCC):c.839C>T (p.Ser280Leu)

gnomAD frequency: 0.00001  dbSNP: rs749230615

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484866	SCV000564976	uncertain significance	not provided	2024-05-08	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with breast cancer (PMID: 35264596); This variant is associated with the following publications: (PMID: Gordon2000[Book], 35264596)
Mendelics	RCV000988211	SCV001137848	uncertain significance	Fanconi anemia complementation group A	2019-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001017686	SCV001178806	likely benign	Hereditary cancer-predisposing syndrome	2019-01-30	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001243848	SCV001417032	uncertain significance	Fanconi anemia	2022-08-27	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 280 of the FANCC protein (p.Ser280Leu). This variant is present in population databases (rs749230615, gnomAD 0.05%). 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: 418188). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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	RCV000484866	SCV001747599	uncertain significance	not provided	2021-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003409651	SCV004114434	uncertain significance	FANCC-related disorder	2023-05-09	criteria provided, single submitter	clinical testing	The FANCC c.839C>T variant is predicted to result in the amino acid substitution p.Ser280Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.043% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-97897632-G-A). In ClinVar, this variant has conflicting interpretations ranging from uncertain to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/418188/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.