Submissions for variant NM_032444.4(SLX4):c.2975G>A (p.Gly992Glu)

gnomAD frequency: 0.00049  dbSNP: rs139287784

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000679857	SCV000396850	uncertain significance	Fanconi anemia complementation group P	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV000351349	SCV000547444	benign	Fanconi anemia	2024-01-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000679857	SCV000807207	uncertain significance	Fanconi anemia complementation group P	2017-09-01	criteria provided, single submitter	clinical testing	Possible pathogenicity based on finding it once in our laboratory in trans with another variant in an 8-year-old female with limb reduction defects, mild malar hypoplasia, retrognathia, bluish slerae, mild language delay
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000679857	SCV001984595	likely benign	Fanconi anemia complementation group P	2020-08-18	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV002223834	SCV002010190	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001820946	SCV002067960	uncertain significance	not specified	2022-01-19	criteria provided, single submitter	clinical testing	DNA sequence analysis of the SLX4 gene demonstrated a sequence change, c.2975G>A, in exon 12 which results in an amino acid change, p.Gly992Glu. This sequence change does not appear to have been previously described in patients with SLX4-related disorders and has been described in the gnomAD database with a frequency of 0.14% in the Ashkenazi Jewish sub-population (dbSNP rs139287784). The p.Gly992Glu change affects a moderately conserved amino acid residue located in a domain of the SLX4 protein that is not known to be functional. The p.Gly992Glu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to contrasting evidences and the lack of functional studies, the clinical significance of this sequence changes remains unknown at this time.
AiLife Diagnostics, AiLife Diagnostics	RCV002223834	SCV002502253	uncertain significance	not provided	2022-03-17	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000351349	SCV002529316	uncertain significance	Fanconi anemia	2021-11-29	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003391153	SCV004120962	uncertain significance	SLX4-related disorder	2023-07-11	criteria provided, single submitter	clinical testing	The SLX4 c.2975G>A variant is predicted to result in the amino acid substitution p.Gly992Glu. This variant has been reported in several large cohorts of patients with hereditary breast and ovarian cancer (Catucci et al. 2012. PubMed ID: 22383991; De Garibay et al. 2013. PubMed ID: 23211700; Shah et al. 2013. PubMed ID: 23840564; Song et al. 2021. PubMed ID: 32546565) but has also been detected in control populations of ostensibly healthy individuals (Song et al. 2021. PubMed ID: 32546565). Additionally, this variant is reported in 0.14% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-3640664-C-T) and has conflicting interpretations in ClinVar ranging from Uncertain to Benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/319162/). Although we suspect that 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.