ClinVar Genomic variation as it relates to human health

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.

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

The frequency of this variant in the general population, 0.0018 (46/26126 chromosomes in Swedish subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with colorectal cancer and leiomyosarcoma (PMID: 32659967 (2020)), breast cancer (PMID: 30086788 (2018)), and ovarian cancer (PMID: 32546565 (2021)). The variant has also been reported in an individual with Fanconi Anemia (PMID: 22778927 (2012)) as well as unaffected individuals (PMID: 14695169 (2003), 29641532 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

Variant summary: FANCA c.3430C>T (p.Arg1144Trp) 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 0.00079 in 1,607,004 control chromosomes, predominantly at a frequency of 0.001 within the Non-Finnish European subpopulation in the gnomAD database (v4 dataset), including 2 homozygotes. This frequency is not higher than the estimated maximum expected for a pathogenic variant in FANCA causing Fanconi Anemia (0.0022), however, the presence of the variant in homozygotes, suggests that it might be benign when found in homozygous state. On the other hand, the variant c.3430C>T, has been reported in the literature in a compound heterozygous individual affected with Fanconi Anemia (Gille_2012), who carried a likely pathogenic FANCA variant, although the phase of these variants was not provided. In addition, the variant has been reported in heterozygous state in patients affected with breast cancer and other tumor phenotypes (e.g Penkert_2018, de Angelis de Carvalho_2020). These reports do not provide unequivocal conclusions about association of the variant with Fanconi Anemia. 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: 22778927, 30086788, 32659967). ClinVar contains an entry for this variant (Variation ID: 408171). Based on the evidence outlined above, the variant was classified as uncertain significance.

Curator: Arleen D. Auerbach. Submitter to LOVD: Johan de Winter.

The FANCA c.3430C>T variant is predicted to result in the amino acid substitution p.Arg1144Trp. This variant has been reported in the compound heterozygous state with a truncating FANCA variant in an individual with Fanconi anemia (Gille et al. 2012. PubMed ID: 22778927). This variant has also been reported in an individual with breast cancer (Penkert et al. 2018. PubMed ID: 30086788) and a family with Lynch syndrome for which there was an alternate molecular cause (Pirini et al. 2019. PubMed ID: 31655866). This variant is reported in 0.093% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of pathogenicity in ClinVar ranging from likely benign to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/408171). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.