ClinVar Genomic variation as it relates to human health
NM_020937.4(FANCM):c.1972C>T (p.Arg658Ter)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_020937.4(FANCM):c.1972C>T (p.Arg658Ter)
Variation ID: 444327 Accession: VCV000444327.36
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 14q21.2 14: 45167133 (GRCh38) [ NCBI UCSC ] 14: 45636336 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 1, 2018 Mar 10, 2024 Dec 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_020937.4:c.1972C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_065988.1:p.Arg658Ter nonsense NM_001308133.2:c.1894C>T NP_001295062.1:p.Arg632Ter nonsense NM_001308134.2:c.1972C>T NP_001295063.1:p.Arg658Ter nonsense NC_000014.9:g.45167133C>T NC_000014.8:g.45636336C>T NG_007417.1:g.36201C>T LRG_502:g.36201C>T LRG_502t1:c.1972C>T - Protein change
- R658*, R632*
- Other names
- -
- Canonical SPDI
- NC_000014.9:45167132:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00020 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00007
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00008
The Genome Aggregation Database (gnomAD) 0.00009
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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FANCM | - | - |
GRCh38 GRCh37 |
2315 | 2359 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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Dec 27, 2023 | RCV000705743.8 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 1, 2023 | RCV000513240.21 | |
Likely pathogenic (1) |
criteria provided, single submitter
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- | RCV001293940.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 25, 2021 | RCV002256327.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Aug 25, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002527323.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Spermatogenic failure 28
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Study: CSER-TexasKidsCanSeq
Accession: SCV001482642.2 First in ClinVar: Mar 07, 2021 Last updated: Mar 18, 2023 |
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Pathogenic
(Nov 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002011493.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
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Likely pathogenic
(Oct 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002496384.3
First in ClinVar: Apr 08, 2022 Last updated: Nov 25, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed as apparently homozygous or as compound heterozygous with a second FANCM truncating variant in individuals with early-onset breast cancer, childhood ALL, non-obstructive azoospermia, or premature ovarian failure (PMID: 28837162, 31942822, 34568721, 34976027); Published functional studies demonstrate a damaging effect: impairment of DNA repair activity and chromosome stability, and absent protein expression (PMID: 31700994); Observed in individuals with polycythemia, breast cancer, or ovarian cancer (PMID: 21681190, 26822949, 28033443, 29351780, 31223512, 30613976, 33099839, 28837162); This variant is associated with the following publications: (PMID: 28033443, 29351780, 21681190, 28881617, 29287190, 30676620, 26822949, 32054657, 30613976, 33099839, 31223512, 28837162, 32427313, 34584094, 33471991, 35441217, 26689913, 34976027, 34568721, 31942822, 33804961, 34308104, 31700994, 32191290) (less)
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Pathogenic
(Dec 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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Fanconi anemia
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000834756.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg658*) in the FANCM gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg658*) in the FANCM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FANCM are known to be pathogenic (PMID: 29895858, 30075111). This variant is present in population databases (rs368728266, gnomAD 0.02%). This variant has been observed to be homozygous in an individual with breast cancer and other oncological malignancies and in an individual with breast cancer, pancytopenia, and chromosome fragility (PMID: 28837162). In addition, this variant has been observed to be heterozygous in individuals affected with ovarian cancer, polycythemia vera, and breast cancer (PMID: 21681190, 26822949, 29351780, 29287190, 28033443, 28881617); and in a large case-control study, this variant was observed more frequently in individuals with ER-negative breast cancer (OR=2.44, 95% CI [1.12-5.34], p=0.034) or triple-negative breast cancer (OR=3.79, 95% CI [1.56-9.18], p=0.009) than among controls (PMID: 31700994). ClinVar contains an entry for this variant (Variation ID: 444327). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental data suggest that this variant might not result in nonsense-mediated mRNA decay. However, experimental studies showed that it 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. (less)
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Likely pathogenic
(Dec 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV000608699.24
First in ClinVar: Oct 30, 2017 Last updated: Mar 10, 2024 |
Comment:
FANCM: PS4, PS3:Moderate, PVS1:Moderate
Number of individuals with the variant: 5
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
The Spectrum of FANCM Protein Truncating Variants in European Breast Cancer Cases. | Figlioli G | Cancers | 2020 | PMID: 31991861 |
The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer. | Figlioli G | NPJ breast cancer | 2019 | PMID: 31700994 |
A homozygous FANCM frameshift pathogenic variant causes male infertility. | Yin H | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 29895858 |
Bi-allelic Recessive Loss-of-Function Variants in FANCM Cause Non-obstructive Azoospermia. | Kasak L | American journal of human genetics | 2018 | PMID: 30075111 |
FANCM and RECQL genetic variants and breast cancer susceptibility: relevance to South Poland and West Ukraine. | Nguyen-Dumont T | BMC medical genetics | 2018 | PMID: 29351780 |
A possible role of FANCM mutations in male breast cancer susceptibility: Results from a multicenter study in Italy. | Silvestri V | Breast (Edinburgh, Scotland) | 2018 | PMID: 29287190 |
Individuals with FANCM biallelic mutations do not develop Fanconi anemia, but show risk for breast cancer, chemotherapy toxicity and may display chromosome fragility. | Catucci I | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 28837162 |
Germline whole exome sequencing and large-scale replication identifies FANCM as a likely high grade serous ovarian cancer susceptibility gene. | Dicks E | Oncotarget | 2017 | PMID: 28881617 |
Association Between Loss-of-Function Mutations Within the FANCM Gene and Early-Onset Familial Breast Cancer. | Neidhardt G | JAMA oncology | 2017 | PMID: 28033443 |
Hereditary truncating mutations of DNA repair and other genes in BRCA1/BRCA2/PALB2-negatively tested breast cancer patients. | Lhota F | Clinical genetics | 2016 | PMID: 26822949 |
Patterns and functional implications of rare germline variants across 12 cancer types. | Lu C | Nature communications | 2015 | PMID: 26689913 |
Structural insights into the functions of the FANCM-FAAP24 complex in DNA repair. | Yang H | Nucleic acids research | 2013 | PMID: 24003026 |
Architecture and DNA recognition elements of the Fanconi anemia FANCM-FAAP24 complex. | Coulthard R | Structure (London, England : 1993) | 2013 | PMID: 23932590 |
Rare germline variants in regions of loss of heterozygosity may influence clinical course of hematological malignancies. | Harutyunyan A | Leukemia | 2011 | PMID: 21681190 |
FANCM-FAAP24 and FANCJ: FA proteins that metabolize DNA. | Ali AM | Mutation research | 2009 | PMID: 19379763 |
Cell cycle-dependent chromatin loading of the Fanconi anemia core complex by FANCM/FAAP24. | Kim JM | Blood | 2008 | PMID: 18174376 |
Identification of FAAP24, a Fanconi anemia core complex protein that interacts with FANCM. | Ciccia A | Molecular cell | 2007 | PMID: 17289582 |
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Text-mined citations for rs368728266 ...
HelpRecord last updated Mar 11, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.