Submissions for variant NM_000136.3(FANCC):c.395C>G (p.Ala132Gly)

gnomAD frequency: 0.00005  dbSNP: rs587779905

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115352	SCV000149261	uncertain significance	not provided	2024-05-30	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 35264596, 26689913, Gordon2000[Book], 33471991)
Illumina Laboratory Services, Illumina	RCV000709093	SCV000481137	uncertain significance	Fanconi anemia complementation group C	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000315029	SCV000549945	uncertain significance	Fanconi anemia	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 132 of the FANCC protein (p.Ala132Gly). This variant is present in population databases (rs587779905, gnomAD 0.006%). 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: 127541). 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.
Ambry Genetics	RCV000571052	SCV000673320	likely benign	Hereditary cancer-predisposing syndrome	2018-11-28	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.
Mendelics	RCV003492473	SCV001137856	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818267	SCV002068029	uncertain significance	not specified	2021-04-16	criteria provided, single submitter	clinical testing	This sequence change does not appear to have been previously described in patients with FANCC-related disorders and has been described in the gnomAD database with a low population frequency of 0.0032% (dbSNP rs587779905). The p.Ala132Gly change affects a poorly conserved amino acid residue located in a domain of the FANCC protein that is known to be functional. The p.Ala132Gly substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ala132Gly change remains unknown at this time.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001818267	SCV004099687	uncertain significance	not specified	2023-09-11	criteria provided, single submitter	clinical testing	Variant summary: FANCC c.395C>G (p.Ala132Gly) 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 3.2e-05 in 251186 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.395C>G has been reported in the literature in individuals affected with Breast Cancer or undertaking multiple gene panel testing, without strong evidence of causality (example, Guindalini_2022, Lu_2015). It is also present in both breast cancer cases and controls in a large study by the Breast Cancer Association Consortium (Dorling_2021). These report(s) do 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: 35264596, 26689913, 33471991). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=6, Likely benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.