Submissions for variant NM_020937.4(FANCM):c.5791C>T (p.Arg1931Ter)

gnomAD frequency: 0.00088  dbSNP: rs144567652

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000630904	SCV000751877	pathogenic	Fanconi anemia	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1931*) in the FANCM gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs144567652, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with non-obstructive azoospermia and breast cancer. Additionally, in a case-control study this variant has been reported as a potential breast cancer risk factor in Southwestern Europeans (OR = 3.93, 95% CI [1.28–12.11], P = 0.017), and has been observed more frequently in individuals with triple-negative breast cancer in the Finnish population (OR= 5.14, 95% CI [1.65–16.0], P = 0.005) (PMID: 26130695, 28702895, 28837162, 30075111). ClinVar contains an entry for this variant (Variation ID: 526381). Experimental studies have shown that this sequence change can result in the skipping of exon 22, and that an exon 22 deletion variant could not rescue mitomycin C sensitivity or a diepoxybutane-induced chromosome fragility phenotype in a FANCM-deficient mouse fibroblast line (PMID: 26130695). This variant disrupts the C-terminal ERCC4 nuclease domain and the helix-hairpin-helix (HhH) motifs of the FANCM protein, which are critical for the interaction between FANCM and FAAP24, chromatin localization of the FANCM/FAAP24 complex and the activation of the FA core complex (PMID: 17289582, 23932590, 18174376, 19379763, 24003026). While functional studies have not been performed to directly test the effect of this variant on FANCM protein function, this suggests that disruption of this region of the protein may be causative of disease. For these reasons, this variant has been classified as Pathogenic.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000722040	SCV000853217	pathogenic	Malignant germ cell tumor of ovary	2018-06-12	criteria provided, single submitter	clinical testing	This is a nonsense alteration in which a C is replaced by a T at coding nucleotide 5791 and is predicted to change an Arginine to a premature stop codon at amino acid codon 1931. Classification criteria: PVS1, PS3.
Division of Medical Genetics, University of Washington	RCV001250442	SCV001424818	pathogenic	Familial cancer of breast	2019-04-10	criteria provided, single submitter	clinical testing	The p.Arg1931* variant is a pathogenic, low penetrance variant in the FANCM gene which is associated with an increased risk to develop breast cancer (PMID: 23409019, 26130695, 28033443). Individuals with the p.Arg1931* variant have an odds ratio of approximately 2-4 for breast cancer (PMID: 26130695, 28033443). This variant results in the deletion of exon 22 from the FANCM protein (PMID: 26130695). This variant occurs at a frequency higher than expected for a fully penetrant pathogenic variant. It has been observed 286 times according to the gnomAD database. Based on the data available at this time, the p.Arg1931* variant is considered to be a pathogenic, low penetrance variant associated with an increased risk for breast cancer.
Baylor Genetics	RCV000677277	SCV001481668	pathogenic	Spermatogenic failure 28		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001531186	SCV001746190	pathogenic	not provided	2021-07-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001531186	SCV001819725	likely pathogenic	not provided	2023-09-27	criteria provided, single submitter	clinical testing	Nonsense variant demonstrated to create a splicing defect resulting in skipping of exon 22 and protein truncation (Peterlongo et al., 2015; Penther et al., 2019); Published functional studies suggest a damaging effect: impaired DNA repair activities, cell survival, and chromosome stability (Peterlongo et al., 2015; Bogliolo et al., 2018; Figlioli et al., 2019); Case-control studies suggest this variant is associated with presence of triple negative or familial breast cancer (Peterlongo et al., 2015; Kiiski et al., 2017), but association with unselected breast cancer was not statistically significant (Gracia-Aznarez et al., 2013; Kiiski et al., 2017; Figlioli et al., 2019; Li et al., 2021); Observed in the homozygous state in adults with cancer, chemotherapy toxicity, and/or reduced fertility, but without other features of Fanconi anemia (Catucci et al., 2018; Kasak et al., 2018; Kherraf et al., 2022); Observed in the heterozygous state in individuals with breast, ovarian, colorectal, and other cancers (Smith et al., 2013; Broderick et al., 2017; Dicks et al., 2017; Nurmi et al., 2019; Earl et al., 2020; Figlioli et al., 2020; Cavaille et al., 2021); Segregated with colorectal cancer in two kindreds, but under further review with a case-control study this variant did not reach a statistically significant association with colorectal cancer (Cannon-Albright et al., 2020); This variant is associated with the following publications: (PMID: 23585368, 26822949, 26130695, 23409019, 28702895, 28881617, 28687971, 28837162, 29287190, 30075111, 30267214, 30426508, 28591191, 28033443, 30779244, 27713038, 30927251, 28837157, 31078449, 25078778, 31700994, 29560538, 30676620, 32113160, 32235514, 31991861, 33036707, 33099839, 34426522, 32338768, 33118316, 33804961, 33809641, 31345219, 34308104, 31263571, 34117267, 35172124, 35739278, 36944283)
Revvity Omics, Revvity	RCV001531186	SCV002017722	likely pathogenic	not provided	2022-02-22	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001821777	SCV002070481	uncertain significance	not specified	2020-01-10	criteria provided, single submitter	clinical testing	DNA sequence analysis of the FANCM gene demonstrated a sequence change, c.5791C>T, which results in the creation of a premature stop codon at amino acid position 1931, p.Arg1931*. This sequence change has been described in the gnomAD database with the relatively high population frequency of 0.46% in European populations (dbSNP rs144567652). The p.Arg1931* change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated FANCM protein with potentially abnormal function. This sequence change has previously been described in patients with breast, pancreatic, ovarian, and colorectal cancer, although the statistical significance of some of these findings remain uncertain (PMIDs: 28702895, 28837162, 26822949, 30426508, 23409019, 28687971, 28591191, 30267214, 23585368). In another case control study of male breast cancer, the p.Arg1931* change was only identified in unaffected male controls (PMID: 29287190). Functional analyses demonstrate that the p.Arg1931* change does not appear to rescue DNA repair-associated phenotypes in a FANCM-deficient mouse fibroblast line (PMID: 26130695). Due to these contrasting evidences, the clinical significance of the p.Arg1931* change remains unknown at this time.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002245059	SCV002512620	pathogenic	Hereditary nonpolyposis colorectal carcinoma	2021-07-13	criteria provided, single submitter	clinical testing	ACMG classification criteria: PVS1 very strong, PM1 moderate, PM3 supporting
Mendelics	RCV000677277	SCV002519704	pathogenic	Spermatogenic failure 28	2022-05-04	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001531186	SCV004218830	pathogenic	not provided	2021-12-30	criteria provided, single submitter	clinical testing	This nonsense variant has been experimentally shown to induce aberrant splicing, which results in the skipping of FANCM exon 22 and the premature termination of FANCM protein synthesis (PMID: 26130695 (2015)). In the published literature, it has been reported in individuals with breast, ovarian, colorectal cancer, melanoma, and in healthy controls (PMIDs: 33471991 (2021), 34117267 (2021), 32235514 (2020), 31991861 (2020), 33118316 (2020), 30426508 (2018), 28591191 (2017), 23409019 (2013)). Several case-control studies characterized this variant as a low penetrance, moderate-risk allele associated with certain subtypes of breast cancer (PMIDs: 31700994 (2019), 28702895 (2017), 26130695 (2015)). Individuals homozygous for this variant presented with breast cancer or azoospermia, but not Fanconi anemia (PMIDs: 28837162 (2018), 30075111 (2018)). In addition, cell line-based functional studies indicated the variant has deleterious effects on cell survival, DNA repair, and chromosome fragility (PMIDs: 31700994 (2019), 26130695 (2015), 23932590 (2013)). Due to possible founder effects, this variant is enriched in the general European/Finnish population (http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as a pathogenic variant with reduced penetrance.
OMIM	RCV000677277	SCV000803410	pathogenic	Spermatogenic failure 28	2018-08-14	no assertion criteria provided	literature only
Genetics of Infertility and Preimplantation Genetic Diagnosis, Centre Hospitalier Universitaire Grenoble Alpes	RCV001797115	SCV002039167	pathogenic	Azoospermia	2021-12-20	no assertion criteria provided	case-control