ClinVar Miner

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

gnomAD frequency: 0.00104  dbSNP: rs147021911
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 12
Download table as spreadsheet
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 ( 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 ( 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

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.