rs147021911

Positions:

chr14-45189123-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). 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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12U:1

Conservation

PhyloP100: 0.927

Variant links:

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 links:

FANCM (HGNC:):

FANCM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 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 [Likely_pathogenic]. Clinvar id is 412519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-45189123-C-T is described in Lovd as [Likely_benign]. Variant chr14-45189123-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCM	NM_020937.4 linkuse as main transcript	c.5101C>T	p.Gln1701*	stop_gained	20/23	ENST00000267430.10	NP_065988.1	Q8IYD8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCM	ENST00000267430.10 linkuse as main transcript	c.5101C>T	p.Gln1701*	stop_gained	20/23	1	NM_020937.4	ENSP00000267430.5		Q8IYD8-1

Frequencies

GnomAD3 genomes

AF:

0.000985

AC:

150

AN:

152210

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.00125

AC:

313

AN:

251238

Hom.:

AF XY:

0.00127

AC XY:

172

AN XY:

135806

show subpopulations

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 SAS 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.:

Cov.:

AF XY:

0.000932

AC XY:

678

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00957

Gnomad4 NFE exome

AF:

0.000738

Gnomad4 OTH exome

AF:

0.000878

GnomAD4 genome

AF:

0.000985

AC:

150

AN:

152328

Hom.:

Cov.:

AF XY:

0.00133

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.0000721

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00820

Gnomad4 NFE

AF:

0.000838

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.000824

Hom.:

Bravo

AF:

0.000314

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00130

AC:

158

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000654

EpiControl

AF:

0.000356

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4Uncertain:1

Uncertain significance, flagged submission	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	FANCM: PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 24, 2022	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 03, 2024	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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 21, 2022	- -

Premature ovarian failure 15

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 31, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 23, 2024	- -

Male infertility with spermatogenesis disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Laan Lab, Human Genetics Research Group, University of Tartu

Sep 01, 2023

- -

Fanconi anemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

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 protein 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. -

Fanconi anemia complementation group A

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

FANCM-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 01, 2024

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

Pathogenic, criteria provided, single submitter

clinical testing

Division of Medical Genetics, University of Washington

Apr 01, 2019

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

DANN

Uncertain

0.98

Eigen

Benign

0.18

Eigen_PC

Benign

-0.21

FATHMM_MKL

Benign

0.31

Vest4

0.79

ClinPred

0.16

GERP RS

-2.5

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over