14-45198718-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 16P and 1B. PVS1PP5_Very_StrongBS1_Supporting

The NM_020937.4(FANCM):c.5791C>T(p.Arg1931*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000951 in 1,613,868 control chromosomes in the GnomAD database, including 4 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 0.00081 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00096 ( 4 hom. )

Consequence

FANCM
NM_020937.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15U:1

Conservation

PhyloP100: 3.41

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 14-45198718-C-T is Pathogenic according to our data. Variant chr14-45198718-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 526381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-45198718-C-T is described in Lovd as [Pathogenic]. Variant chr14-45198718-C-T is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000815 (124/152200) while in subpopulation NFE AF= 0.000926 (63/68014). AF 95% confidence interval is 0.000742. There are 0 homozygotes in gnomad4. There are 65 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCM	NM_020937.4 link	c.5791C>T	p.Arg1931*	stop_gained	Exon 22 of 23	ENST00000267430.10	NP_065988.1	Q8IYD8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCM	ENST00000267430.10 link	c.5791C>T	p.Arg1931*	stop_gained	Exon 22 of 23	1	NM_020937.4	ENSP00000267430.5		Q8IYD8-1

Frequencies

GnomAD3 genomes

AF:

0.000815

AC:

124

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00378

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000926

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.00101

AC:

254

AN:

251330

Hom.:

AF XY:

0.000972

AC XY:

132

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.00448

Gnomad NFE exome

AF:

0.00106

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000965

AC:

1410

AN:

1461668

Hom.:

Cov.:

AF XY:

0.000970

AC XY:

705

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000559

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000186

Gnomad4 FIN exome

AF:

0.00331

Gnomad4 NFE exome

AF:

0.00101

Gnomad4 OTH exome

AF:

0.000993

GnomAD4 genome

AF:

0.000815

AC:

124

AN:

152200

Hom.:

Cov.:

AF XY:

0.000874

AC XY:

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00378

Gnomad4 NFE

AF:

0.000926

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000946

Hom.:

Bravo

AF:

0.000597

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000881

AC:

107

EpiCase

AF:

0.00142

EpiControl

AF:

0.00130

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Dec 30, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This nonsense variant has been experimentally shown to induce aberrant splicing, which results in the skipping of FANCM exon 22 and the premature termination of FANCM protein synthesis (PMID: 26130695 (2015)). In the published literature, it has been reported in individuals with breast, ovarian, colorectal cancer, melanoma, and in healthy controls (PMIDs: 33471991 (2021), 34117267 (2021), 32235514 (2020), 31991861 (2020), 33118316 (2020), 30426508 (2018), 28591191 (2017), 23409019 (2013)). Several case-control studies characterized this variant as a low penetrance, moderate-risk allele associated with certain subtypes of breast cancer (PMIDs: 31700994 (2019), 28702895 (2017), 26130695 (2015)). Individuals homozygous for this variant presented with breast cancer or azoospermia, but not Fanconi anemia (PMIDs: 28837162 (2018), 30075111 (2018)). In addition, cell line-based functional studies indicated the variant has deleterious effects on cell survival, DNA repair, and chromosome fragility (PMIDs: 31700994 (2019), 26130695 (2015), 23932590 (2013)). 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 a pathogenic variant with reduced penetrance. -

Feb 22, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FANCM: PVS1, PS4:Moderate -

Nov 05, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant demonstrated to create a splicing defect resulting in skipping of exon 22 and protein truncation (PMID: 30779244, 26130695); Observed in the homozygous state in adults with cancer, chemotherapy toxicity, and/or reduced fertility, but without other features of Fanconi anemia (PMID: 28837162, 30075111, 35172124); Observed in the heterozygous state in individuals with breast, ovarian, colorectal, and other cancers (PMID: 23585368, 27713038, 28881617, 30927251, 32113160, 31991861, 33099839); Case-control studies suggest this variant is associated with presence of triple negative or familial breast cancer, but association with unselected breast cancer was not statistically significant (PMID: 26130695, 23409019, 28702895, 31700994, 34117267); Segregated with colorectal cancer in two kindreds, but under further review with a case-control study this variant did not reach a statistically significant association with colorectal cancer (PMID: 33118316); Published functional studies suggest a damaging effect: impaired DNA repair activities, cell survival, and chromosome stability (PMID: 28837157, 26130695, 31700994); This variant is associated with the following publications: (PMID: 23585368, 26822949, 26130695, 23409019, 28702895, 28881617, 28687971, 28837162, 29287190, 30075111, 30267214, 30426508, 28591191, 28033443, 30779244, 27713038, 30927251, 28837157, 31078449, 25078778, 31700994, 29560538, 30676620, 32113160, 32235514, 31991861, 33036707, 33099839, 34326862, 36099812, 36732629, 32191290, 37608704, 36551643, 34887416, 34482403, 34426522, 32338768, 33804961, 33809641, 31345219, 34308104, 31263571, 34117267, 35172124, 35739278, 36944283, 38633426, 37450374, 36572685, 34301788, 38846492, 33118316) -

Spermatogenic failure 28

Pathogenic:3

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 17, 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.Arg1931*) in the FANCM gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs144567652, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with non-obstructive azoospermia and breast cancer. 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‚Äì12.11], P = 0.017), and has been observed more frequently in individuals with triple-negative breast cancer in the Finnish population (OR= 5.14, 95% CI [1.65‚Äì16.0], P = 0.005) (PMID: 26130695, 28702895, 28837162, 30075111). 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 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 -

Premature ovarian failure 15

Pathogenic:1

Jul 23, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Spermatogenic failure 28;C4748170:Premature ovarian failure 15

Pathogenic:1

May 24, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant germ cell tumor of ovary

Pathogenic:1

Jun 12, 2018

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Hereditary nonpolyposis colorectal carcinoma

Pathogenic:1

Jul 13, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PVS1 very strong, PM1 moderate, PM3 supporting -

Familial cancer of breast

Pathogenic:1

Apr 10, 2019

Division of Medical Genetics, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Azoospermia

Pathogenic:1

Dec 20, 2021

Genetics of Infertility and Preimplantation Genetic Diagnosis, Centre Hospitalier Universitaire Grenoble Alpes

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

- -

not specified

Uncertain:1

Jan 10, 2020

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

DNA sequence analysis of the FANCM gene demonstrated a sequence change, c.5791C>T, which results in the creation of a premature stop codon at amino acid position 1931, p.Arg1931*. This sequence change has been described in the gnomAD database with the relatively high population frequency of 0.46% in European populations (dbSNP rs144567652). The p.Arg1931* change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated FANCM protein with potentially abnormal function. This sequence change has previously been described in patients with breast, pancreatic, ovarian, and colorectal cancer, although the statistical significance of some of these findings remain uncertain (PMIDs: 28702895, 28837162, 26822949, 30426508, 23409019, 28687971, 28591191, 30267214, 23585368). In another case control study of male breast cancer, the p.Arg1931* change was only identified in unaffected male controls (PMID: 29287190). Functional analyses demonstrate that the p.Arg1931* change does not appear to rescue DNA repair-associated phenotypes in a FANCM-deficient mouse fibroblast line (PMID: 26130695). Due to these contrasting evidences, the clinical significance of the p.Arg1931* change remains unknown at this time. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.83

Vest4

0.91

ClinPred

0.40

GERP RS

5.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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