Submissions for variant NM_020937.4(FANCM):c.269C>T (p.Pro90Leu)

gnomAD frequency: 0.00032  dbSNP: rs142904668

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000382796	SCV000626363	uncertain significance	Fanconi anemia	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 90 of the FANCM protein (p.Pro90Leu). This variant is present in population databases (rs142904668, gnomAD 0.06%). This missense change has been observed in individual(s) with head and neck squamous cell carcinoma (PMID: 28678401). ClinVar contains an entry for this variant (Variation ID: 313189). 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. 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.
GeneDx	RCV001660632	SCV001874867	uncertain significance	not provided	2023-08-30	criteria provided, single submitter	clinical testing	Observed in individuals with ovarian and other cancers (Chandrasekharappa et al., 2017; Dicks et al., 2017); 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: 28678401, 27713038, 28881617)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001660632	SCV002011490	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001820926	SCV002067111	uncertain significance	not specified	2020-12-15	criteria provided, single submitter	clinical testing	DNA sequence analysis of the FANCM gene demonstrated a sequence change, c.269C>T, in exon 1 that results in an amino acid change, p.Pro90Leu. This sequence change has been previously described in a patient with head and neck squamous cell carcinoma (PMID: 28678401) but no other details are available. It has been described in the gnomAD database with a population frequency of 0.062% in the non-Finnish European subpopulation (dbSNP rs142904668). The p.Pro90Leu change affects a moderately conserved amino acid residue located in a domain of the FANCM protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Pro90Leu substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Pro90Leu change remains unknown at this time.
Fulgent Genetics, Fulgent Genetics	RCV002480130	SCV002778016	uncertain significance	Spermatogenic failure 28; Premature ovarian failure 15	2022-05-04	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003940213	SCV004748566	uncertain significance	FANCM-related condition	2023-11-02	criteria provided, single submitter	clinical testing	The FANCM c.269C>T variant is predicted to result in the amino acid substitution p.Pro90Leu. This variant was reported in an individual with head and neck squamous cell carcinoma and in another individual with polyps, who also carried a POLE variant (Supplementary Table 3, Chandrasekharappa et al 2017. PubMed ID: 28678401; Table S4, Bhai. 2021. PubMed ID: 34326862), however it was also identified in a control population (Table S7, Dicks et al. 2017. PubMed ID: 28881617). This variant is reported in 0.062% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-45605503-C-T) and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/313189/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.