Submissions for variant NM_032444.4(SLX4):c.832C>T (p.Arg278Trp)

gnomAD frequency: 0.00014  dbSNP: rs141597706

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000534649	SCV000626454	uncertain significance	Fanconi anemia	2022-10-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 278 of the SLX4 protein (p.Arg278Trp). This variant is present in population databases (rs141597706, gnomAD 0.08%). This missense change has been observed in individual(s) with cancer (PMID: 23211700, 30306255, 30613976). ClinVar contains an entry for this variant (Variation ID: 456338). 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: "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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001290535	SCV001478590	uncertain significance	not specified	2022-11-03	criteria provided, single submitter	clinical testing	Variant summary: BTBD12 (also known as SLX4) c.832C>T (p.Arg278Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 282844 control chromosomes, predominantly at a frequency of 0.00085 within the Latino subpopulation in the gnomAD database. c.832C>T has been reported in the literature in individuals affected with breast/ovarian cancer and with renal cancer (e.g. de Garibay_2013, Bonache_2018, Lee_2018, Rizzolo_2019). These reports do not provide unequivocal conclusions about association of the variant with Fanconi Anemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003237892	SCV002009224	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000534649	SCV002529395	uncertain significance	Fanconi anemia	2021-12-17	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV001764528	SCV002793748	uncertain significance	Fanconi anemia complementation group P	2022-02-16	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001764528	SCV003823918	uncertain significance	Fanconi anemia complementation group P	2019-11-18	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV003237892	SCV004144927	likely benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing	SLX4: BP4