ClinVar Miner

Submissions for variant NM_020937.4(FANCM):c.5101C>T (p.Gln1701Ter) (rs147021911)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000456962 SCV000554073 pathogenic Fanconi anemia 2019-12-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln1701*) in the FANCM gene. It is expected to result in an absent or disrupted protein product, although an experimental study has shown that this variant does not cause nonsense-mediated mRNA decay (PMID: 25288723). This variant is present in population databases (rs147021911, ExAC 0.9% in the Finnish population), including one individual from the Finnish population that was homozygous for this variant. This variant has been observed to be homozygous in an individual affected with idiopathic non-obstructive azoospermia and hypergonadotropic hypogonadism (PMID: 30075111), and an individual with breast cancer and early menopause (PMID: 28837162). In addition, it has been observed to segregate with non-syndromic primary ovarian insufficiency in the homozygous state in an affected family (PMID: 29231814). ClinVar contains an entry for this variant (Variation ID: 412519). In the Finnish population this variant has been observed more frequently in individuals with breast cancer 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). This variant disrupts the C-terminal domain of the FANCM protein, including the entire ERCC4 nuclease domain and the helix-hairpin-helix (HhH) motifs. These domains are critical for the interaction between FANCM and its DNA-binding partner FAAP24, as well as chromatin localization of the FANCM/FAAP24 complex and the activation of the FA core complex (PMID: 17289582, 23932590, 18174376, 19379763, 24003026). This variant has been reported to affect FANCM protein function (PMID: 31700994). In summary, this variant has been observed in the homozygous state in individuals affected with infertility, and therefore has been classified as Pathogenic. When in the heterozygous state, this variant is associated with increased risk for breast cancer.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000585292 SCV000692787 pathogenic not provided 2020-06-01 criteria provided, single submitter clinical testing
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.
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
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785432 SCV000924004 pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research

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