Submissions for variant NM_032444.4(SLX4):c.2681T>G (p.Val894Gly)

gnomAD frequency: 0.00036  dbSNP: rs145137472

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001027802	SCV000396859	uncertain significance	Fanconi anemia complementation group P	2018-01-12	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	RCV000362095	SCV000626412	uncertain significance	Fanconi anemia	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 894 of the SLX4 protein (p.Val894Gly). This variant is present in population databases (rs145137472, gnomAD 0.1%). This missense change has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 22911665, 32546565). ClinVar contains an entry for this variant (Variation ID: 319164). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glycine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
CeGaT Center for Human Genetics Tuebingen	RCV000762181	SCV000892449	uncertain significance	not provided	2018-07-01	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001027802	SCV001190415	uncertain significance	Fanconi anemia complementation group P	2021-03-30	criteria provided, single submitter	clinical testing	SLX4 NM_032444.3 exon 12 p.Val894Gly (c.2681T>G): This variant has not been reported in the literature and is present in 0.1% (11/10370) of Ashkenazi Jewish alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-3640958-A-C). This variant is present in ClinVar (Variation ID:319164). This variant amino acid Glycine (Gly) is present in multiple mammals and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
GeneDx	RCV000762181	SCV001800985	uncertain significance	not provided	2022-10-17	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, as well as in healthy controls (Bakker et al., 2013; Song et al., 2021); This variant is associated with the following publications: (PMID: 22911665, 32546565)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000762181	SCV002010257	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000362095	SCV002529309	uncertain significance	Fanconi anemia	2022-01-26	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194828	SCV004241754	uncertain significance	not specified	2023-12-28	criteria provided, single submitter	clinical testing	Variant summary: BTBD12 c.2681T>G (p.Val894Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00033 in 282824 control chromosomes (gnomAD). c.2681T>G has been reported in the literature in individuals affected with breast cancer and/or ovarian cancer (examples: Bakker_2012, Song_2019). These report(s) 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. The following publications have been ascertained in the context of this evaluation (PMID: 22911665, 36916425, 32546565). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Leiden Open Variation Database	RCV001194828	SCV001364633	likely benign	not specified	2012-08-31	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Janine Bakker.