rs147021911

Variant names:

• chr14-45189123-C-T
• rs147021911
• NM_020937.4:c.5101C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 16P and 5B. PVS1 PP5_Very_Strong BS1_Supporting BS2

The NM_020937.4(FANCM):​c.5101C>T​(p.Gln1701*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000955 in 1,613,978 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q1701Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00098 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00095 (2 hom.)
• Consequence: FANCM NM_020937.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15 U:1
• Conservation: PhyloP100: 0.927
• Publications: 63 publications found

Genes affected

FANCM (HGNC:23168): (FA complementation group M) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group M. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

FANCM Gene-Disease associations (from GenCC):

• Fanconi anemia

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: G2P, Orphanet
• spermatogenic failure 28

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 14-45189123-C-T is Pathogenic according to our data. Variant chr14-45189123-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 412519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000985 (150/152328) while in subpopulation NFE AF = 0.000838 (57/68028). AF 95% confidence interval is 0.000664. There are 1 homozygotes in GnomAd4. There are 99 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCM	NM_020937.4	c.5101C>T	p.Gln1701*	stop_gained	Exon 20 of 23	ENST00000267430.10	NP_065988.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCM	ENST00000267430.10	c.5101C>T	p.Gln1701*	stop_gained	Exon 20 of 23	1	NM_020937.4	ENSP00000267430.5

Frequencies

GnomAD3 genomes AF: 0.000985 AC: 150 AN: 152210 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00820

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.00125 AC: 313 AN: 251238 AF XY: 0.00127

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00822

Gnomad NFE exome AF: 0.00104

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.000952 AC: 1391 AN: 1461650 Hom.: 2 Cov.: 32 AF XY: 0.000932 AC XY: 678 AN XY: 727146

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00957 AC: 511 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000738 AC: 821 AN: 1111806

Other (OTH) AF: 0.000878 AC: 53 AN: 60376

GnomAD4 genome AF: 0.000985 AC: 150 AN: 152328 Hom.: 1 Cov.: 32 AF XY: 0.00133 AC XY: 99 AN XY: 74478

African (AFR) AF: 0.0000721 AC: 3 AN: 41588

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00820 AC: 87 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000838 AC: 57 AN: 68028

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000863 Hom.: 0

Bravo AF: 0.000314

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00130 AC: 158

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000356

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4 Uncertain:1

Dec 03, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 348 amino acids are lost, with studies suggesting the truncated protein escapes nonsense-mediated decay (PMID: 25288723, 29231814); Published functional studies suggest a damaging effect: increased chromosome fragility, decreased cell survival, and reduced monoubiquination of FANCM in response to MMC and DEB exposure (PMID: 29231814, 31700994); Observed in the homozygous or compound heterozygous state in individuals without classic Fanconi anemia, but with bone marrow failure, chemotherapy toxicity, or reduced fertility (PMID: 29231814, 28837162, 30075111, 31942822); Observed in multiple individuals with breast cancer and incompletely segregates with disease in several affected families (PMID: 25288723, 26822949, 29231814, 28033443, 30426508, 31882575, 31991861, 34326862); Some case-control studies support an association with breast cancer, primarily with triple negative or ER negative disease (PMID: 25288723, 31700994, 36747679); This variant is associated with the following publications: (PMID: 24459294, 32054657, 25288723, 26822949, 27153395, 28678401, 28837162, 28702895, 28033443, 29231814, 30075111, 30426508, 26130695, 28837157, 29287190, 28881617, 27226120, 26067930, 28874143, 27542569, 30927251, 26740942, 25078778, 19423727, 16116422, 31700994, 30877237, 31882575, 29895858, 31991861, 32183364, 31942822, 26689913, 31263571, 33099839, 33025164, 32338768, 31589614, 34117267, 32099950, 32300589, 32467344, 31936873, 32680567, 32381463, 33804961, 34308104, 31345219, 35441217, 23932590, 17289582, 36551643, 24003026, 18174376, 19379763, 36901862, 36980738, 36099812, 36835452, 35802266, 36315097, 36747679, 29053726, 34887416, 35739278, 34326862, 33471991, 38614076) -

Apr 24, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This nonsense variant causes the premature termination of FANCM protein synthesis, however, experimental studies suggest that this variant may not lead to nonsense mediated decay (PMIDs: 25288723 (2014) and 29231814 (2017)). In the published literature, the variant has been reported in affected individuals with breast cancer (PMIDs: 26822949 (2016), 28837162 (2018), and 30426508 (2018)), prostate cancer (PMID: 32338768 (2020), and cervical, colorectal, and pancreatic cancers (PMID: 31263571 (2019)), as well as in controls (PMID: 33471991 (2021)). In the homozygous state, it has been associated with azoospermia and primary ovarian insufficiency (PMIDs: 29231814 (2017) and 30075111 (2018)). When seen with another pathogenic FANCM variant, bone marrow failure was observed (PMID: 32054657 (2020)). Functional studies found that this variant increased chromosome fragility, decreased DNA repair activity, and absent protein expression (PMIDs: 29231814 (2017) and 31700994 (2019)). Segregation for this variant was found to be inconclusive (PMIDs: 25288723 (2014), 28033443 (2017), and 28837162 (2018)). Due to possible founder effects, this variant is enriched in the general European/Finnish population (http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic with reduced penetrance. -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Oct 21, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FANCM: PVS1, PS4:Moderate -

Premature ovarian failure 15 Pathogenic:2

Aug 31, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 23, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Fanconi anemia Pathogenic:2

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln1701*) in the FANCM gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 348 amino acid(s) of the FANCM protein. This variant is present in population databases (rs147021911, gnomAD 0.8%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with breast cancer significantly more often 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). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 412519). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal 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. -

Feb 04, 2025

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1 -

Spermatogenic failure 28;C4748170:Premature ovarian failure 15 Pathogenic:2

Nov 09, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Jan 09, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Male infertility with spermatogenesis disorder Pathogenic:1

Sep 01, 2023

Laan Lab, Human Genetics Research Group, University of Tartu

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Fanconi anemia complementation group A Pathogenic:1

May 28, 2019

Mendelics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

FANCM-related disorder Pathogenic:1

May 01, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FANCM c.5101C>T variant is predicted to result in premature protein termination (p.Gln1701*). This variant has been reported in individuals with breast cancer and/or ovarian cancer (Kiiski et al. 2014. PubMed ID: 25288723; Lhota et al. 2016. PubMed ID: 26822949; Catucci et al. 2017. PubMed ID: 28837162; Schubert et al. 2019. PubMed ID: 30426508; Figlioli et al. 2020. PubMed ID: 31991861). This variant has also been reported in the homozygous state in patients with non-syndromic primary ovarian insufficiency (Fouquet et al. 2017. PubMed ID: 29231814) and non-obstructive azoospermia (Kasak et al. 2018. PubMed ID: 30075111). This variant is reported in 0.81% of alleles in individuals of European (Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from uncertain to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/412519/). Nonsense variants in FANCM are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Familial cancer of breast Pathogenic:1

Apr 01, 2019

Division of Medical Genetics, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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 (http://exac.broadinstitute.org/) 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. -

Spermatogenic failure 28 Pathogenic:1

Jul 23, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	35
DANN	Uncertain	0.98
Eigen	Benign	0.18
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.31	N
PhyloP100		0.93
Vest4		0.79
ClinPred		0.16	T
GERP RS		-2.5
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs147021911; hg19: chr14-45658326; COSMIC: COSV57498280; COSMIC: COSV57498280;