Submissions for variant NM_000143.4(FH):c.557G>A (p.Ser186Asn)

dbSNP: rs587782618

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131997	SCV000187056	likely pathogenic	Hereditary cancer-predisposing syndrome	2016-01-22	criteria provided, single submitter	clinical testing	The p.S186N variant (also known as c.557G>A), located in coding exon 5 of the FH gene, results from a G to A substitution at nucleotide position 557. The serine at codon 186 is replaced by asparagine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.02% (greater than 10000 alleles tested) in our clinical cohort. This alteration has been detected in multiple families with a history of cutaneous leiomyomas and renal cancers (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002514749	SCV001221688	pathogenic	not provided	2023-10-03	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 186 of the FH protein (p.Ser186Asn). This variant is present in population databases (rs587782618, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of hereditary leiomyomatosis and renal cell cancer (PMID: 31444830, 35163394; external communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 142654). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects FH function (PMID: 35163394). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV004567146	SCV005057781	likely pathogenic	Fumarase deficiency	2023-11-04	criteria provided, single submitter	clinical testing
Institutes of Biomedical Sciences, Shanxi University	RCV001029752	SCV001189984	pathogenic	Hereditary leiomyomatosis and renal cell cancer	2019-06-13	no assertion criteria provided	case-control	The Ser186Asn variant has not been reported in the literature so far. In our study, a Chinese female patient carrying Ser186Asn variant was affected with autosomal dominant uterine leiomyomas (multiple). Additionally, our in vitro functional studies indicate that the Ser186Asn reduced the enzyme activity and disrupts normal function. In summary, the Ser186Asn variant meets our criteria to be classified as pathogenic based upon segregation studies, absence from controls, and functional evidence.