rs759217526

Positions:

• chr2-58159793-G-GTAAT

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PVS1_Moderate BS2

The NM_018062.4(FANCL):​c.1099_1100insATTA​(p.Thr367AsnfsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00365 in 1,612,828 control chromosomes in the GnomAD database, including 21 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0030 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (18 hom.)
• Consequence: FANCL NM_018062.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:13 B:4
• Conservation: PhyloP100: 2.00

Genes affected

FANCL (HGNC:20748): (FA complementation group L) This gene encodes a ubiquitin ligase that is a member of the Fanconi anemia complementation group (FANC). Members of this group are related by their assembly into a common nuclear protein complex rather than by sequence similarity. This gene encodes the protein for complementation group L that mediates monoubiquitination of FANCD2 as well as FANCI. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2018]

VRK2 (HGNC:12719): (VRK serine/threonine kinase 2) This gene encodes a member of the vaccinia-related kinase (VRK) family of serine/threonine protein kinases. The encoded protein acts as an effector of signaling pathways that regulate apoptosis and tumor cell growth. Variants in this gene have been associated with schizophrenia. Alternative splicing results in multiple transcript variants that differ in their subcellular localization and biological activity. [provided by RefSeq, Jan 2014]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0257 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCL	NM_018062.4	c.1099_1100insATTA	p.Thr367AsnfsTer13	frameshift_variant	14/14	ENST00000233741.9	NP_060532.2
VRK2	NM_006296.7	c.*102_*105dup		3_prime_UTR_variant	13/13	ENST00000340157.9	NP_006287.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCL	ENST00000233741.9	c.1099_1100insATTA	p.Thr367AsnfsTer13	frameshift_variant	14/14	1	NM_018062.4	ENSP00000233741	P4
VRK2	ENST00000340157.9	c.*102_*105dup		3_prime_UTR_variant	13/13	1	NM_006296.7	ENSP00000342381	P1

Frequencies

GnomAD3 genomes AF: 0.00299 AC: 455 AN: 151950 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000556

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00387

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00265

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00422

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00301 AC: 750 AN: 249062 Hom.: 4 AF XY: 0.00308 AC XY: 416 AN XY: 134996

Gnomad AFR exome AF: 0.000766

Gnomad AMR exome AF: 0.00535

Gnomad ASJ exome AF: 0.00669

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000754

Gnomad FIN exome AF: 0.00181

Gnomad NFE exome AF: 0.00350

Gnomad OTH exome AF: 0.00497

GnomAD4 exome AF: 0.00372 AC: 5434 AN: 1460760 Hom.: 18 Cov.: 31 AF XY: 0.00372 AC XY: 2702 AN XY: 726652

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00466

Gnomad4 ASJ exome AF: 0.00789

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000708

Gnomad4 FIN exome AF: 0.00179

Gnomad4 NFE exome AF: 0.00414

Gnomad4 OTH exome AF: 0.00381

GnomAD4 genome AF: 0.00299 AC: 455 AN: 152068 Hom.: 3 Cov.: 32 AF XY: 0.00274 AC XY: 204 AN XY: 74320

Gnomad4 AFR AF: 0.000554

Gnomad4 AMR AF: 0.00387

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00265

Gnomad4 NFE AF: 0.00422

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00406 Hom.: 0

Bravo AF: 0.00318

EpiCase AF: 0.00415

EpiControl AF: 0.00427

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:13 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:6 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	FANCL: BS2; VRK2: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Feb 24, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 01, 2023	Observed in the heterozygous state, sometimes using alternate nomenclature (c.1095_1098dupAATT, c.1094_1095insAATT, or c.1100_1100C>ATTAC), in multiple individuals with cancer, including breast cancer, head and neck squamous cell carcinoma, childhood-onset solid tumors, and lung adenocarcinoma (Akbari et al., 2011; Ellingson et al., 2015; Lhota et al., 2016; Parsons et al., 2016; Tedaldi et al., 2017; Chandrasekharappa et al., 2017; Ghazani et al., 2017); Frameshift variant predicted to result in protein truncation as the last 9 amino acids are replaced with 12 different amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 19405097, 27506598, 26822237, 28125075, 26822949, 27659787, 28423363, 28678401, 26296701, 30306255, 32235514, 27153395, 33504652, 34585473, 35929646, 21279724, 36268089, 34308104, 36135330) -

Fanconi anemia complementation group L Pathogenic:2 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 10, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Daryl Scott Lab, Baylor College of Medicine	Aug 22, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2009	- -
Likely pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	Jul 20, 2019	Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Zdenek Kleibl. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Apr 28, 2021	FANCL NM_018062.3 exon 14 p.Thr367Asnfs*13 (c.1096_1099dup): This variant has been reported in the literature in the compound heterozygous state in one individual with mild features of fanconi anemia (Ali 2009 PMID:19405097). It has also been reported in the heterozygous state in association with multiple different types of cancers (breast, lung adendocarcinoma, pediatric solid tumors, esophageal, head and neck squamous cell carcinoma) (Akbari 2011 PMID:21279724, Lhota 2016 PMID:26822949, Parsons 2016 PMID:26822237, Chandrasekharappa 2017 PMID:28678401, Ghazani 2017 PMID:28125075, del Valle 2020 PMID:32235514). However, this variant is also present in 0.4% (287/67948) of European alleles in the Genome Aggregation Database, including 3 homozygotes (https://gnomad.broadinstitute.org/variant/2-58159793-G-GTAAT?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:210989). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is a frameshift variants that removes the final termination codon and extends out the protein. Further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Fanconi anemia Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jun 04, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	The c.1111_1114dupATTA (p.Thr372AsnfsTer13) variant, which results in a frameshift near the C-terminus of the protein and extends the full-length protein by ten amino acids, was observed in a patient with clinical features suggestive of Fanconi anemia (Ali et al. 2009). This patient was compound heterozygous for the p.Thr372AsnfsTer13 variant, which was inherited from the patient's father, and a second inframe deletion variant that was inherited from the patient's mother. Functional testing of this variant, when ectopically expressed in FA-L patient cell line, resulted in a phenotype intermediate of EUFA868 cells expressing vector alone and EUFA868 cells expressing wild-type FANCL. The p.Thr372AsnfsTer13 variant has been reported at a frequency of 0.00783 in the population described as 'Other' in the Exome Aggregation Consortium. The evidence for this variant is limited. Based on the evidence from the literature and due to the potential impact of frameshift variants, the p.Thr372AsnfsTer13 variant is classified as a variant of uncertain significance but suspicious for pathogenicity for Fanconi anemia. -

not specified Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 22, 2022	Variant summary: FANCL c.1096_1099dupATTA (p.Thr367AsnfsX13) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 0.003 in 249062 control chromosomes in the gnomAD database, including 4 homozygotes. Truncations downstream of this variant have not been observed at our laboratory and not reported in association with Fanconi Anemia in the HGMD/LOVD database. The observed variant frequency is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in FANCL causing Fanconi Anemia phenotype (0.00028), strongly suggesting that the variant is benign. Although widely reported in the literature, to our knowledge, no penetrant association of c.1096_1099dupATTA in individuals affected with Fanconi Anemia and no supporting experimental evidence demonstrating its impact on protein function have been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments and one submitter reporting a pathogenic classification has since re-classified it internally as Benign (Benign, n=2; VUS, n=6). Based on the evidence outlined above, the variant was classified as benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 02, 2019	- -

Fanconi anemia complementation group A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

FANCL-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 23, 2024

The FANCL c.1111_1114dupATTA variant is predicted to result in a frameshift and premature protein termination (p.Thr372Asnfs*13). In the literature, this variant is also referred to as c.1095_1908dupAATT (p.Thr367Asnfs*13) and c.1111_1114dup p.(Thr372Asnfs*13).This variant has been reported in the heterozygous state in an individual with esophageal squamous cell carcinoma (ESCC) and a family history of ESCC (Patient P28266, Akbari et al. 2011. PubMed ID: 21279724) and in an individual with ovarian cancer (Patient ID 13-285, Bonache et al. 2018. PubMed ID: 30306255). This variant was also identified in several individuals in a study of variants in Fanconi anemia genes in hereditary cancer patients, however this study considered the cancer risk cancer for monoallelic carriers of this variant to be limited (Supplementary Tables, Del Valle et al. 2020. PubMed ID: 32235514). In a study of individuals with primary ovarian insufficiency, this variant was found in the homozygous and heterozygous states in individuals with no clinical features of Fanconi anemia and this variant was thought to be unlikely causative of the ovarian phenotype in these individuals (Table 3, POI-24 and POI-44, Franca et al. 2020 PubMedID: 33095795). This variant was also reported in a cohort of Fanconi anemia patients and another cohort of hereditary breast and ovarian cancer patients, however this variant was reported to be co-inherited with variants in other genes (Supplementary Tables 3 and 4, Chandrasekharappa et al. 2017. PubMed ID: 28678401; Supplementary Table 3, Tedaldi et al. 2017. PubMed ID: 28423363). This variant is reported in 0.68% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from pathogenic to uncertain significance to likely benign to benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/210988/). While this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs759217526; hg19: chr2-58386928;