Submissions for variant NM_032444.4(SLX4):c.2305G>C (p.Glu769Gln)

gnomAD frequency: 0.00119  dbSNP: rs150712805

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000463301	SCV000547438	uncertain significance	Fanconi anemia	2022-10-31	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 769 of the SLX4 protein (p.Glu769Gln). This variant is present in population databases (rs150712805, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with breast cancer or head and neck carcinoma (PMID: 23211700, 23840564, 28678401). ClinVar contains an entry for this variant (Variation ID: 407899). 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: "Tolerated"; PolyPhen-2: "Possibly 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.
Illumina Laboratory Services, Illumina	RCV001121834	SCV001280487	uncertain significance	Fanconi anemia complementation group P	2017-04-27	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	RCV001121834	SCV001481518	uncertain significance	Fanconi anemia complementation group P	2020-12-04	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	RCV001796060	SCV002010301	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001821253	SCV002067993	uncertain significance	not specified	2021-11-22	criteria provided, single submitter	clinical testing	This sequence change has been reported in familial breast cancer cases(PMID: 23840564). This sequence change has been described in the gnomAD database with a frequency of 0.16% in the non-Finnish subpopulation (dbSNP rs150712805). The p.Glu769Gln change affects a poorly conserved amino acid residue located in a domain of the SLX4 protein that is known to be functional. The p.Glu769Gln substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Glu769Gln change remains unknown at this time.
GeneDx	RCV001796060	SCV002104461	uncertain significance	not provided	2022-03-03	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer in published literature (Shah 2013); This variant is associated with the following publications: (PMID: 19596235, 23840564)
Sema4, Sema4	RCV000463301	SCV002529297	uncertain significance	Fanconi anemia	2021-09-03	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV001121834	SCV002782458	uncertain significance	Fanconi anemia complementation group P	2022-05-04	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001121834	SCV003823914	uncertain significance	Fanconi anemia complementation group P	2019-10-14	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001796060	SCV002033923	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001796060	SCV002038379	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003902645	SCV004722456	likely benign	SLX4-related disorder	2022-04-22	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).