ClinVar Miner

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

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000456962 SCV000554073 risk factor Fanconi anemia 2018-12-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 1701 (p.Gln1701*) of 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. In the Finnish population this variant was 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/moderate-risk allele (PMID: 25288723). When survival effects were analyzed among familial breast cancer cases, carriers of this variant exhibited a poorer 10-year survival rate than affected individuals not carrying this variant (hazard ratio = 2.93, 95% CI [1.5-5.76], p=0.0018) (PMID: 27542569). This variant has not been reported in the literature in individuals affected with Fanconi anemia. Although an association between loss-of-function variants in FANCM and Fanconi anemia has been suggested (PMID: 16116422), that suggestion has since been challenged in subsequent publications (PMID: 25078778, 19423727, 26740942). ClinVar contains an entry for this variant (Variation ID: 412519). In summary, this is a frequently observed variant in the Finnish population that is associated with a 2- to 3.5-fold increased risk for breast cancer. However, the association of this variant, and the FANCM gene generally, with Fanconi anemia is uncertain at this time.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000585292 SCV000692787 likely pathogenic not provided 2017-10-31 criteria provided, single submitter clinical testing
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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