Submissions for variant NM_020937.4(FANCM):c.2809C>T (p.Leu937Phe)

gnomAD frequency: 0.00017  dbSNP: rs138274490

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000823317	SCV000964171	uncertain significance	Fanconi anemia	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 937 of the FANCM protein (p.Leu937Phe). This variant is present in population databases (rs138274490, gnomAD 0.08%). 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: 665106). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The phenylalanine 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.
Baylor Genetics	RCV001293944	SCV001482646	uncertain significance	Spermatogenic failure 28	2020-01-22	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV001772139	SCV002001238	uncertain significance	not provided	2023-05-08	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics	RCV002478929	SCV002784984	uncertain significance	Spermatogenic failure 28; Premature ovarian failure 15	2022-02-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002535981	SCV003691764	likely benign	Inborn genetic diseases	2022-09-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
PreventionGenetics, part of Exact Sciences	RCV004538129	SCV004115306	uncertain significance	FANCM-related disorder	2023-04-20	criteria provided, single submitter	clinical testing	The FANCM c.2809C>T variant is predicted to result in the amino acid substitution p.Leu937Phe. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.077% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-45644766-C-T), which is more common than expected for a primary cause of disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.