ClinVar Genomic variation as it relates to human health

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

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.

Variant summary: FANCC c.632C>G (p.Pro211Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0013 in 249292 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in FANCC causing Fanconi Anemia Group C (0.0013 vs 0.0018), allowing no conclusion about variant significance. c.632C>G has been reported in the literature in individuals with a personal and/or family history of cancer without evidence of cosegregation with disease (e.g. Thompson_2012, Bhai_2021). These reports 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: 23028338, 34326862). ClinVar contains an entry for this variant (Variation ID: 127544). Based on the evidence outlined above, the variant was classified as uncertain significance.

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.

Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.

The FANCC p.Pro211Arg variant was identified in 3 of 2744 proband chromosomes (frequency: 0.001) from individuals or families with leukaemia or Alzheimer’s Disease and was present in 2 of 1362 control chromosomes (Balmana 2016, Barber 2003, Kim 2016). The variant was also identified in dbSNP (ID: rs140781259) as "With other allele ", ClinVar (classified as benign by Invitae; as likely benign by GeneDx; as uncertain significance by two submitters), MutDB, and in LOVD 3.0. The variant was not identified in Cosmic database. The variant was identified in control databases in 382 of 275066 chromosomes (1 homozygous) at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 7 of 23782 chromosomes (freq: 0.0003), Other in 8 of 6438 chromosomes (freq: 0.001), Latino in 8 of 34190 chromosomes (freq: 0.0002), European in 150 of 125766 chromosomes (freq: 0.001), Finnish in 208 of 25744 chromosomes (freq: 0.008), and South Asian in 1 of 30286 chromosomes (freq: 0.00003); it was not observed in the Ashkenazi Jewish, and in East Asian populations. The p.Pro211 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).