ClinVar Miner

Submissions for variant NM_020937.4(FANCM):c.5791C>T (p.Arg1931Ter) (rs144567652)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000630904 SCV000751877 pathogenic Fanconi anemia 2020-01-01 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1931*) 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 may not cause nonsense-mediated mRNA decay (PMID: 26130695). This variant is present in population databases (rs144567652, ExAC 0.5%). This variant has been observed to be homozygous in an individual affected with non-obstructive azoospermia (PMID: 30075111), and an individual with breast cancer and early menopause (PMID: 28837162). 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) (PMID: 26130695), 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: 28702895). 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 domain of the FANCM protein, including a portion of the ERCC4 nuclease domain and the entire 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 suggests that disruption of this region of the protein may be causative of disease. 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.
Clinical Genomics Lab,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.
OMIM RCV000677277 SCV000803410 pathogenic SPERMATOGENIC FAILURE 28 2018-08-14 no assertion criteria provided literature only

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