Submissions for variant NM_032444.4(SLX4):c.1372A>G (p.Lys458Glu)

gnomAD frequency: 0.00087  dbSNP: rs149126845

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001088147	SCV000547477	benign	Fanconi anemia	2024-01-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000519850	SCV000620201	uncertain significance	not provided	2022-11-28	criteria provided, single submitter	clinical testing	Observed in an individual with seizures and developmental delay who was de novo for a variant in the SLC1A2 gene as well as compound heterozygous for the K458E variant and another SLX4 missense variant; however follow up testing for Fanconi anemia was normal (Guella et al., 2017); Identified in individuals with breast, ovarian, or head/neck cancers, but also observed in controls (Shah et al., 2013; Bakker et al. 2013; Chandrasekharappa et al., 2017; Rizzolo et al., 2019; Song et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23840564, 32546565, 28678401, 22911665, 30613976, 28777935)
Fulgent Genetics, Fulgent Genetics	RCV000764064	SCV000895018	uncertain significance	Fanconi anemia complementation group P	2018-10-31	criteria provided, single submitter	clinical testing
Mendelics	RCV003492056	SCV001139916	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000519850	SCV001150772	uncertain significance	not provided	2017-12-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000764064	SCV001280599	uncertain significance	Fanconi anemia complementation group P	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Baylor Genetics	RCV000764064	SCV001481709	uncertain significance	Fanconi anemia complementation group P	2019-06-19	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000519850	SCV002010737	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001194850	SCV002068071	uncertain significance	not specified	2020-01-13	criteria provided, single submitter	clinical testing	DNA sequence analysis of the SLX4 gene demonstrated a sequence change, c.1372A>G, in exon 7 that results in an amino acid change, p.Lys458Glu. This sequence change has been previously described in a patient with breast cancer, however there is not enough evidence to support the pathogenicity of this sequence change in these studies (PMID: 22911665 and PMID: 23840564). This sequence change has been described in the gnomAD database with a low population frequency of 0.075% (dbSNP rs149126845). The p.Lys458Glu change affects a highly conserved amino acid residue located in a domain of the SLX4 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Lys458Glu substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Lys458Glu change remains unknown at this time.
Sema4, Sema4	RCV001088147	SCV002529257	likely benign	Fanconi anemia	2021-04-07	criteria provided, single submitter	curation
Leiden Open Variation Database	RCV001194850	SCV001364681	likely benign	not specified	2012-08-31	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Janine Bakker.