Submissions for variant NM_020937.4(FANCM):c.5101C>T (p.Gln1701Ter)

gnomAD frequency: 0.00104  dbSNP: rs147021911

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000456962	SCV000554073	pathogenic	Fanconi anemia	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1701*) in the FANCM gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 348 amino acid(s) of the FANCM protein. This variant is present in population databases (rs147021911, gnomAD 0.8%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with breast cancer significantly more often than among controls (OR=1.86, 95% CI [1.26-2.75], p=0.0018), especially for individuals with familial breast cancer (OR=2.11, 95% CI [1.34-3.32], p=0.0012) or triple-negative breast cancer (OR=3.56, 95% CI [1.81-6.98], p=0.0002). When segregation studies were performed in 45 individuals from 8 breast cancer families carrying this variant, most of the families showed incomplete segregation with disease. These results are consistent with this variant being a low-to moderate-risk allele (PMID: 25288723). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 412519). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects FANCM function (PMID: 31700994). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000585292	SCV000692787	likely pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	FANCM: PVS1
Mendelics	RCV000989212	SCV001139441	likely pathogenic	Fanconi anemia complementation group A	2019-05-28	criteria provided, single submitter	clinical testing
Division of Medical Genetics, University of Washington	RCV001250424	SCV001424775	pathogenic	Familial cancer of breast	2019-04-01	criteria provided, single submitter	clinical testing	The c.5101C>T nonsense variant creates a premature stop codon; however, functional studies suggest this variant may not lead to nonsense mediated decay (Kiiski 2014). The c.5101C>T variant has an allele frequency of 0.0009 in the Broad Institute ExAC Browser (http://exac.broadinstitute.org/) and is more common in individuals from the Finnish population (Kiiski 2014). The c.5101C>T variant has been reported more frequently in individuals with breast cancer than controls, particularly in patients with familial breast cancer or triple negative breast cancer, and is associated with a 2.5-3 fold increased risk for breast cancer. The c.5101C>T variant has also shown incomplete segregation with disease (Kiiski 2014). Evidence is conflicting regarding if being compound heterozygous or homozygous for pathogenic variants in FANCM causes Fanconi Anemia (Singh 2009, Lim 2014, Meetei 2015, Nicchia 2015]. To our knowledge, this variant has not been reported in an individual with Fanconi Anemia. Thus, the c.5101C>T variant is a pathogenic, low penetrance variant associated with an increased risk for breast cancer.
GeneDx	RCV000585292	SCV001817166	likely pathogenic	not provided	2023-10-27	criteria provided, single submitter	clinical testing	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 348 amino acids are lost, with studies suggesting the truncated protein escapes nonsense-mediated decay (PMID: 25288723, 29231814); Published functional studies suggest a damaging effect: increased chromosome fragility, decreased cell survival, and reduced monoubiquination of FANCM in response to MMC and DEB exposure (PMID: 29231814, 31700994); Observed in the homozygous or compound heterozygous state in individuals without classic Fanconi anemia, but with bone marrow failure, chemotherapy toxicity, or reduced fertility (PMID: 29231814, 28837162, 30075111, 31942822); Observed in multiple individuals with breast cancer and incompletely segregates with disease in several affected families (PMID: 25288723, 26822949, 29231814, 28033443, 30426508, 31882575, 31991861, 34326862); Some case-control studies support an association with breast cancer, primarily with triple negative or ER negative disease (PMID: 25288723, 31700994, 36747679); This variant is associated with the following publications: (PMID: 24459294, 32054657, 25288723, 26822949, 27153395, 28678401, 28837162, 28702895, 28033443, 29231814, 30075111, 30426508, 26130695, 28837157, 29287190, 28881617, 27226120, 26067930, 28874143, 27542569, 30927251, 26740942, 25078778, 19423727, 16116422, 31700994, 30877237, 31882575, 29895858, 31991861, 32183364, 31942822, 26689913, 31263571, 33099839, 33025164, 32338768, 31589614, 34117267, 32099950, 32300589, 32467344, 31936873, 32680567, 32381463, 33804961, 34308104, 31345219, 35441217, 23932590, 17289582, 36551643, 24003026, 18174376, 19379763, 36901862, 36980738, 36099812, 36835452, 35802266, 36315097, 36747679, 29053726, 34887416, 34326862, 35739278)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000585292	SCV002011472	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000585292	SCV003832845	likely pathogenic	not provided	2022-10-21	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000678209	SCV004197292	pathogenic	Premature ovarian failure 15	2022-08-31	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000585292	SCV004218815	pathogenic	not provided	2022-04-24	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of FANCM protein synthesis, however, experimental studies suggest that this variant may not lead to nonsense mediated decay (PMIDs: 25288723 (2014) and 29231814 (2017)). In the published literature, the variant has been reported in affected individuals with breast cancer (PMIDs: 26822949 (2016), 28837162 (2018), and 30426508 (2018)), prostate cancer (PMID: 32338768 (2020), and cervical, colorectal, and pancreatic cancers (PMID: 31263571 (2019)), as well as in controls (PMID: 33471991 (2021)). In the homozygous state, it has been associated with azoospermia and primary ovarian insufficiency (PMIDs: 29231814 (2017) and 30075111 (2018)). When seen with another pathogenic FANCM variant, bone marrow failure was observed (PMID: 32054657 (2020)). Functional studies found that this variant increased chromosome fragility, decreased DNA repair activity, and absent protein expression (PMIDs: 29231814 (2017) and 31700994 (2019)). Segregation for this variant was found to be inconclusive (PMIDs: 25288723 (2014), 28033443 (2017), and 28837162 (2018)). 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 pathogenic with reduced penetrance.
Laan Lab, Human Genetics Research Group, University of Tartu	RCV003991578	SCV004239192	pathogenic	Male infertility with spermatogenesis disorder	2023-09-01	criteria provided, single submitter	research
OMIM	RCV000677276	SCV000803409	pathogenic	Spermatogenic failure 28	2018-08-27	no assertion criteria provided	literature only
OMIM	RCV000678209	SCV000804211	pathogenic	Premature ovarian failure 15	2018-08-27	no assertion criteria provided	literature only