Submissions for variant NM_020937.4(FANCM):c.1237T>C (p.Tyr413His)

gnomAD frequency: 0.00086  dbSNP: rs138225703

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000688866	SCV000816493	uncertain significance	Fanconi anemia	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 413 of the FANCM protein (p.Tyr413His). This variant is present in population databases (rs138225703, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer (PMID: 30426508). ClinVar contains an entry for this variant (Variation ID: 568489). 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 tolerated. 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.
Fulgent Genetics, Fulgent Genetics	RCV000763928	SCV000894872	uncertain significance	Spermatogenic failure 28; Premature ovarian failure 15	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001535656	SCV001805174	uncertain significance	not provided	2024-10-14	criteria provided, single submitter	clinical testing	Observed in individuals with breast, ovarian, or colorectal cancer, and also in unaffected controls (PMID: 27713038, 28881617, 30426508, 34326862); 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: 30426508, 27713038, 28881617, 34326862)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001535656	SCV002011503	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001771942	SCV002030206	uncertain significance	Spermatogenic failure 28	2021-02-09	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Sema4, Sema4	RCV002256466	SCV002527310	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-08	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001535656	SCV004218714	likely benign	not provided	2022-07-13	criteria provided, single submitter	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV001535656	SCV001749710	not provided	not provided		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 04-02-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
PreventionGenetics, part of Exact Sciences	RCV004535713	SCV004119874	uncertain significance	FANCM-related disorder	2024-05-09	no assertion criteria provided	clinical testing	The FANCM c.1237T>C variant is predicted to result in the amino acid substitution p.Tyr413His. This variant has been reported in an individuals with breast cancer and/or ovarian cancer, and it has also been reported in controls (Supplemental Table 2, Schubert et al. 2019. PubMed ID: 30426508; Table S4 in Bhai et al. 2021. PubMed ID: 34326862; Supplemental Material in Broderick et al. 2016. PubMed ID: 27713038). This variant is reported in 0.14% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been interpreted as variant of uncertain significance in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/568489/). 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.