Submissions for variant NM_032444.4(SLX4):c.421G>T (p.Gly141Trp)

dbSNP: rs137976282

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000233422	SCV000291088	likely benign	Fanconi anemia	2024-01-22	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764068	SCV000895022	uncertain significance	Fanconi anemia complementation group P	2018-10-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000989506	SCV001139919	uncertain significance	Fanconi anemia complementation group A	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000764068	SCV001278815	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Baylor Genetics	RCV000764068	SCV001481262	uncertain significance	Fanconi anemia complementation group P	2018-12-17	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. The c.421G>T (p.G141W) variant has been previously reported in patients with breast cancer [PMID 23211700, 23840564]
GeneDx	RCV001570886	SCV001795256	uncertain significance	not provided	2023-08-01	criteria provided, single submitter	clinical testing	Observed in individuals with a personal or family history of breast and other cancers (Shah et al., 2013; de Garibay et al., 2013; Bakker et al., 2013; Fernandez-Rodriguez et al., 2012; Jalkh et al., 2017); Identified in the compound heterozygous state in two siblings with pre-B acute lymphoblastic leukemia; however, these individuals also harbored variants in other genes that may be related to their condition (Spinella et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23840564, 23211700, 22911665, 22401137, 28202063, 26201965, 30995915, 33558524, 28717660, 22383991, 29970176)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001570886	SCV002009379	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001194829	SCV002066156	uncertain significance	not specified	2018-06-05	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000233422	SCV002529343	uncertain significance	Fanconi anemia	2021-10-25	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV001570886	SCV004144930	likely benign	not provided	2023-07-01	criteria provided, single submitter	clinical testing	SLX4: BP4
Center of Medical Genetics and Primary Health Care	RCV001005038	SCV000987295	uncertain significance	Malignant tumor of breast	2020-04-08	no assertion criteria provided	research	ACMG Guidelines 2015 criteria BS1 Benign Strong: GnomAD exomes allele frequency = 0.000819 > 0.000165 derived from the 555 clinically reported variants in gene SLX4 of which 19 pathogenic, 288 uncertain significance and 248 benign. BP1 Benign Supporting: 92 out of 92 non-VUS missense variants in gene SLX4 are benign = 100.0% > threshold of 51.0%, and 248 out of 555 clinically reported variants in gene SLX4 are benign = 44.7% > threshold of 24.0%. BP4 Benign Supporting: 9 benign predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, MVP, MutationAssessor, MutationTaster, PrimateAI and REVEL vs 4 pathogenic predictions from M-CAP, SIFT, PolyPhen-2, Align-GVGD and the position is not conserved. BP6 Benign Supporting: UniProt classifies this variant as polymorphism. This variant has been reported in individuals affected with breast cancer, childhood acute lymphoblastic leukemia, and unspecified cancer types (PMID: 23211700, 23840564, 28202063, 22401137, 26201965, 28717660). Therefore, this variant was classified as a Variant of Unknown Significance.
Leiden Open Variation Database	RCV001194829	SCV001364636	likely benign	not specified	2012-08-31	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Janine Bakker.