ClinVar Genomic variation as it relates to human health

Variant summary: The c. variant involves the alteration of a non-conserved nucleotide and 2/4 in silico tools predict a neutral outcome. The variant is present in the control population dataset of ExAC at frequency of 0.78%, predomintantly observed in the African subpopulation at a frequency of 8%, including 37 homozygous occurrences. The observed frequency greatly exceeds the maximum expected allele frequency for a pathogenic variant of 0.18%, strong evidence that it is a benign polymorphism. Classification of the variant of interest has not been reported by reputable databases/clinical laboratories. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign.

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

This variant is associated with the following publications: (PMID: 30967997, 28135048, 24728327)

This alteration is classified as 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.Val449Met variant was identified in 4 of 912 proband chromosomes (frequency: 0.004) from British/other individuals or families with non-BRCA1/2 breast cancer, Fanconi anemia and leukemia, and was identified in 8 of 1362 control chromosomes from healthy individuals (Gibson 1996, Seal 2003, Barber 2003, Bodian 2014). The variant was also identified in dbSNP (ID: rs1800367) “With other allele”, ClinVar (classified as benign by Prevention Genetics and Invitae; likely benign by Illumina, and unclassified by ITMI), Clinvitae (2X), LOVD 3.0 (1X) but was not identified in Cosmic, and MutDB databases. The variant was identified in control databases in 2071 (76 homozygous) of 276492 chromosomes at a frequency of 0.007 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017) being identified in the following population at a frequency greater than 1%: African in 1753 (74 homozygous) of 23978 chromosomes (freq: 0.07), The p.Val449 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.