VCV000408221.21 - ClinVar

NM_020937.4(FANCM):c.5569G>A (p.Val1857Met)

Germline

Classification

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.

(8)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_020937.4(FANCM):c.5569G>A (p.Val1857Met)

Variation ID: 408221 Accession: VCV000408221.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q21.2 14: 45196400 (GRCh38) [ NCBI UCSC ] 14: 45665603 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	May 26, 2018	Jan 19, 2025	May 14, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_020937.4:c.5569G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_065988.1:p.Val1857Met	missense
NM_001308133.2:c.5491G>A	NP_001295062.1:p.Val1831Met	missense
NM_020937.3:c.5569G>A
NC_000014.9:g.45196400G>A
NC_000014.8:g.45665603G>A
NG_007417.1:g.65468G>A
LRG_502:g.65468G>A
LRG_502t1:c.5569G>A

... more HGVS ... less HGVS

Protein change

V1857M, V1831M

Other names

Canonical SPDI

NC_000014.9:45196399:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.00080 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015

Trans-Omics for Precision Medicine (TOPMed) 0.00037

Exome Aggregation Consortium (ExAC) 0.00038

The Genome Aggregation Database (gnomAD), exomes 0.00043

The Genome Aggregation Database (gnomAD) 0.00049

1000 Genomes Project 30x 0.00078

1000 Genomes Project 0.00080

Links

ClinGen: CA7170021 dbSNP: rs144008013 VarSome

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
Gene	OMIM	HI score Help 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.
FANCM		-	-	GRCh38 GRCh37	2555	2601

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.
Fanconi anemia	Uncertain significance (1)	criteria provided, single submitter	Oct 28, 2022	RCV000465642.15
Premature ovarian failure 15 Spermatogenic failure 28	Uncertain significance (1)	criteria provided, single submitter	Oct 31, 2018	RCV000765164.9
Fanconi anemia, complementation group M	not provided (1)	no classification provided	-	RCV000709952.8
not provided	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	May 14, 2024	RCV001662428.18
Hereditary cancer-predisposing syndrome	Uncertain significance (1)	criteria provided, single submitter	Oct 19, 2021	RCV002255393.9
FANCM-related disorder	Uncertain significance (1)	no assertion criteria provided	Jul 26, 2024	RCV004737525.1

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.
Uncertain significance (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Spermatogenic failure 28 Premature ovarian failure 15 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000896393.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Uncertain significance (Oct 19, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002529883.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The FANCM c.5569G>A (p.V1857M) variant has been reported in heterozygosity in at least one individual with breast cancer (PMID: 19737859). It was also reported in … (more) The FANCM c.5569G>A (p.V1857M) variant has been reported in heterozygosity in at least one individual with breast cancer (PMID: 19737859). It was also reported in a large breast cancer case-control analysis in 75/60,466 cases and in 57/53,461 controls (PMID: 33471991). It was observed in 88/129164 chromosomes of the Non-Finnish European subpopulation, with one homozygote, in the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID 408221). Functional studies have not been performed, and in silico predictions of the variant's effect on protein function are inconclusive. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)	Publications: PubMed (2) PubMed: 19737859‚ 33471991
Uncertain significance (Oct 28, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Fanconi anemia Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000547802.8 First in ClinVar: Apr 17, 2017 Last updated: Feb 07, 2023	Publications: PubMed (1) PubMed: 19737859 Comment: This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1857 of the FANCM protein (p.Val1857Met). … (more) This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1857 of the FANCM protein (p.Val1857Met). This variant is present in population databases (rs144008013, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer (PMID: 19737859). ClinVar contains an entry for this variant (Variation ID: 408221). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Nov 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002011469.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023
Uncertain significance (May 14, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001875099.7 First in ClinVar: Sep 19, 2021 Last updated: Sep 29, 2024	Comment: Observed in individuals with a personal and/or family history of breast cancer but also in unaffected controls (PMID: 19737859, 33471991, 35802266, 37656691, 34326862); Observed in … (more) Observed in individuals with a personal and/or family history of breast cancer but also in unaffected controls (PMID: 19737859, 33471991, 35802266, 37656691, 34326862); Observed in an individual with cervical cancer and papillary urothelial carcinoma who also had a germline pathogenic variant identified in VHL (PMID: 34628056); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33471991, 26596371, 35802266, 19737859, 34628056, 37656691, 34326862) (less)
Uncertain significance (Nov 20, 2023)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV005626329.1 First in ClinVar: Jan 19, 2025 Last updated: Jan 19, 2025	Publications: PubMed (6) PubMed: 34326862‚ 35802266‚ 34628056‚ 37656691‚ 33471991‚ 19737859 Comment: The FANCM c.5569G>A (p.Val1857Met) variant has been reported in the published literature in individuals with a personal and/or family history of breast cancer (PMID: 19737859 … (more) The FANCM c.5569G>A (p.Val1857Met) variant has been reported in the published literature in individuals with a personal and/or family history of breast cancer (PMID: 19737859 (2009), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/FANCM), 35802266 (2023), 37656691 (2023)). It has also been reported in an individual suspected with hereditary cancer syndrome (PMID: 34326862 (2021)), and in an individual with cervical cancer and papillary urothelial carcinoma (PMID: 34628056 (2021)). Additionally, this variant has been reported in unaffected individuals (PMID: 19737859 (2009), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/FANCM)). The frequency of this variant in the general population, 0.00068 (88/129164 chromosomes in European (Non-Finnish) subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
Uncertain significance (Jul 26, 2024)	no assertion criteria provided Method: clinical testing	FANCM-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005345441.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The FANCM c.5569G>A variant is predicted to result in the amino acid substitution p.Val1857Met. This variant was reported in the heterozygous state in one individual … (more) The FANCM c.5569G>A variant is predicted to result in the amino acid substitution p.Val1857Met. This variant was reported in the heterozygous state in one individual with breast cancer, however it was not classified as a high-risk breast cancer risk allele (García et al. 2009. PubMed ID: 19737859). It is unclear whether this variant may be a primary cause of Fanconi anemia, however it is reported in 0.068% of alleles in individuals of European (Non-Finnish) descent, including one homozygous individual, in gnomAD which may be too high to be causative. This variant is interpreted as variant of uncertain significance in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/408221/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
not provided (-)	no classification provided Method: phenotyping only	Fanconi anemia, complementation group M Affected status: unknown Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV000840312.1 First in ClinVar: Oct 14, 2018 Last updated: Oct 14, 2018	Comment: GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical … (more) GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Clinical Features: Ptosis (present) , Myopia (present) , Abnormality of vision (present) , Abnormality of eye movement (present) , Vertigo (present) , Hyperacusis (present) , Tinnitus (present) … (more) Ptosis (present) , Myopia (present) , Abnormality of vision (present) , Abnormality of eye movement (present) , Vertigo (present) , Hyperacusis (present) , Tinnitus (present) , Seizures (present) , Memory impairment (present) , EEG abnormality (present) , Abnormality of coordination (present) , Morphological abnormality of the central nervous system (present) , Stroke (present) , Hypercholesterolemia (present) , Abnormality of cardiovascular system morphology (present) , Syncope (present) , Abnormal EKG (present) , Arrhythmia (present) , Gastrointestinal dysmotility (present) , Abnormality of the stomach (present) , Abnormality of the bladder (present) , Recurrent infections (present) , Immunodeficiency (present) , Abnormality of leukocytes (present) , Abnormality of erythrocytes (present) , Abnormality of thrombocytes (present) , Abnormal thrombosis (present) , Neoplasm of lung (present) , Neoplasm of uterus (present) , Breast carcinoma (present) (less) Indication for testing: Diagnostic Age: 40-49 years Sex: female Ethnicity/Population group: Caucasians MedGen:C0043157 Testing laboratory: GeneDx Date variant was reported to submitter: 2017-12-15 Testing laboratory interpretation: Uncertain significance

Comment:

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1857 of the FANCM protein (p.Val1857Met). This variant is present in population databases (rs144008013, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer (PMID: 19737859). ClinVar contains an entry for this variant (Variation ID: 408221). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

Observed in individuals with a personal and/or family history of breast cancer but also in unaffected controls (PMID: 19737859, 33471991, 35802266, 37656691, 34326862); Observed in an individual with cervical cancer and papillary urothelial carcinoma who also had a germline pathogenic variant identified in VHL (PMID: 34628056); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33471991, 26596371, 35802266, 19737859, 34628056, 37656691, 34326862)

Comment:

The FANCM c.5569G>A (p.Val1857Met) variant has been reported in the published literature in individuals with a personal and/or family history of breast cancer (PMID: 19737859 (2009), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/FANCM), 35802266 (2023), 37656691 (2023)). It has also been reported in an individual suspected with hereditary cancer syndrome (PMID: 34326862 (2021)), and in an individual with cervical cancer and papillary urothelial carcinoma (PMID: 34628056 (2021)). Additionally, this variant has been reported in unaffected individuals (PMID: 19737859 (2009), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/FANCM)). The frequency of this variant in the general population, 0.00068 (88/129164 chromosomes in European (Non-Finnish) subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

Comment:

The FANCM c.5569G>A variant is predicted to result in the amino acid substitution p.Val1857Met. This variant was reported in the heterozygous state in one individual with breast cancer, however it was not classified as a high-risk breast cancer risk allele (García et al. 2009. PubMed ID: 19737859). It is unclear whether this variant may be a primary cause of Fanconi anemia, however it is reported in 0.068% of alleles in individuals of European (Non-Finnish) descent, including one homozygous individual, in gnomAD which may be too high to be causative. This variant is interpreted as variant of uncertain significance in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/408221/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Investigation of germline variants in Bahraini women with breast cancer using next-generation sequencing based-multigene panel.	Al-Kafaji G	PloS one	2023	PMID: 37656691
Prevalence of FANCM germline variants in BRCA1/2 negative breast and/or ovarian cancer patients from Pakistan.	Rashid MU	Familial cancer	2023	PMID: 35802266
Pathogenicity of VHL variants in families with non-syndromic von Hippel-Lindau phenotypes: An integrated evaluation of germline and somatic genomic results.	Rana HQ	European journal of medical genetics	2021	PMID: 34628056
Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach.	Bhai P	Frontiers in genetics	2021	PMID: 34326862
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
Mutational analysis of FANCL, FANCM and the recently identified FANCI suggests that among the 13 known Fanconi Anemia genes, only FANCD1/BRCA2 plays a major role in high-risk breast cancer predisposition.	García MJ	Carcinogenesis	2009	PMID: 19737859

Text-mined citations for rs144008013 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jan 19, 2025

ClinVar Genomic variation as it relates to human health

NM_020937.4(FANCM):c.5569G>A (p.Val1857Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs144008013 ...