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: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity.

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1456 of the FANCM protein (p.Arg1456Cys). This variant is present in population databases (rs200360968, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with FANCM-related conditions. ClinVar contains an entry for this variant (Variation ID: 313218). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The cysteine 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.

Observed in an individual with familial pulmonary fibrosis and shortened telomeres who also harbored variants in RTEL1 and RAD51C (PMID: 30995915); Observed in individuals with ovarian or other cancers and in unaffected controls (PMID: 27713038, 28881617); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27713038, 29641532, 27525107, 28881617, 30995915, 35982159, 38103590)

FANCM: BP4

The FANCM p.Arg1430Cys variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs200360968), ClinVar (classified as a VUS by Illumina, Invitae and Fulgent Genetics) and LOVD 3.0. The variant was also identified in control databases in 69 of 275248 chromosomes at a frequency of 0.000251 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (Non-Finnish) in 62 of 125766 chromosomes (freq: 0.000493), Other in 2 of 6406 chromosomes (freq: 0.000312), South Asian in 3 of 30664 chromosomes (freq: 0.000098) and Latino in 2 of 34284 chromosomes (freq: 0.000058), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, and European (Finnish) populations. The p.Arg1430 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.