rs144008013

Positions:

• chr14-45196400-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_020937.4(FANCM):​c.5569G>A​(p.Val1857Met) variant causes a missense change. The variant allele was found at a frequency of 0.000717 in 1,614,018 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00049 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00074 (2 hom.)
• Consequence: FANCM NM_020937.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6 O:1
• Conservation: PhyloP100: 4.93

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15004778).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCM	NM_020937.4	c.5569G>A	p.Val1857Met	missense_variant	21/23	ENST00000267430.10	NP_065988.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCM	ENST00000267430.10	c.5569G>A	p.Val1857Met	missense_variant	21/23	1	NM_020937.4	ENSP00000267430	P1

Frequencies

GnomAD3 genomes AF: 0.000493 AC: 75 AN: 152148 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000433 AC: 109 AN: 251448 Hom.: 0 AF XY: 0.000471 AC XY: 64 AN XY: 135894

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.000555

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000615

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000740 AC: 1082 AN: 1461752 Hom.: 2 Cov.: 33 AF XY: 0.000778 AC XY: 566 AN XY: 727176

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000800

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000862

Gnomad4 OTH exome AF: 0.000563

GnomAD4 genome AF: 0.000493 AC: 75 AN: 152266 Hom.: 1 Cov.: 32 AF XY: 0.000510 AC XY: 38 AN XY: 74450

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000794

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000722 Hom.: 0

Bravo AF: 0.000370

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000379 AC: 46

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2024	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) -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Fanconi anemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 28, 2022

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. -

Spermatogenic failure 28;C4748170:Premature ovarian failure 15 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

FANCM-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 26, 2024

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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

Oct 19, 2021

- -

Fanconi anemia, complementation group M Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;.;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.7	M;.;.
MutationTaster	Benign	0.91	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Uncertain	0.37
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.51
MVP		0.54
MPC		0.46
ClinPred		0.096	T
GERP RS		4.4
Varity_R		0.61
gMVP		0.53

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

Other links and lift over

dbSNP: rs144008013; hg19: chr14-45665603;