Submissions for variant NM_000143.4(FH):c.349G>C (p.Ala117Pro)

dbSNP: rs886039363

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255340	SCV000321640	pathogenic	not provided	2017-12-11	criteria provided, single submitter	clinical testing	The A117P missense variant in the FH gene has been reported previously in association with multiple leiomyomatosis (Tomlinson et al., 2002) and type 2 papillary renal cell cancer (Gardie et al., 2011). The A117P variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.
Ambry Genetics	RCV001020456	SCV001181940	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-11-09	criteria provided, single submitter	clinical testing	The p.A117P variant (also known as c.349G>C), located in coding exon 3 of the FH gene, results from a G to C substitution at nucleotide position 349. The alanine at codon 117 is replaced by proline, an amino acid with highly similar properties. This alteration has been described in several individuals with HLRCC (Tomlinson IP et al. Nat. Genet. 2002 Apr;30:406-10; Gardie B et al. J. Med. Genet. 2011 Apr;48:226-34; Picaud S et al. J. Inherit. Metab. Dis. 2011 Jun;34:671-6; Ambry internal data). This alteration was also identified in a patient with a recurrent pheochromocytoma; she also had a hysterectomy at age 35 due to hemorrhagic fibroids (Letouzé E et al. Cancer Cell. 2013 Jun;23:739-52). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This alteration is also called p.Ala74Pro in the literature. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000255340	SCV001400741	pathogenic	not provided	2024-10-07	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 117 of the FH protein (p.Ala117Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with renal cell carcinoma and cutaneous and uterine leiomyomas and pheochromocytoma (PMID: 11865300, 21398687, 24334767, 31831373; internal data). This variant is also known as c.220G>C (p.Ala74Pro). ClinVar contains an entry for this variant (Variation ID: 265146). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt FH protein function with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on FH function (PMID: 11865300, 21398687). For these reasons, this variant has been classified as Pathogenic.
Sema4, Sema4	RCV001020456	SCV002535558	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-18	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV003456040	SCV004187830	likely pathogenic	Hereditary leiomyomatosis and renal cell cancer	2023-07-05	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 24334767, 21398687, 11865300, 33167498, 12761039]. Functional studies indicate this variant impacts protein function [PMID: 16237213]. This variant is expected to disrupt protein structure [Myriad internal data].
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV003456040	SCV005399581	pathogenic	Hereditary leiomyomatosis and renal cell cancer	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive fumarase deficiency (MIM#606812) and autosomal dominant leiomyomatosis and renal cell cancer (MIM#150800). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance, where heterozygous individuals may be severely affected or asymptomatic (PMID: 21398687). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to proline. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated lyase_1 domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic and pathogenic, and observed in at least five individuals with leiomyomas, renal cell cancer or pheochromocytoma. One of these individuals had a somatic second hit (ClinVar, PMID: 33167498, PMID: 31831373, PMID: 28300276, PMID: 24334767). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign