Submissions for variant NM_058216.3(RAD51C):c.233C>T (p.Thr78Ile)

gnomAD frequency: 0.00001  dbSNP: rs112832782

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000231279	SCV000291216	uncertain significance	Fanconi anemia complementation group O	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 78 of the RAD51C protein (p.Thr78Ile). This variant is present in population databases (rs112832782, gnomAD 0.09%). This missense change has been observed in individual(s) with breast cancer and/or pancreatic cancer (PMID: 36562461). ClinVar contains an entry for this variant (Variation ID: 241767). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect RAD51C function (PMID: 36562461). 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.
GeneDx	RCV000236604	SCV000292675	uncertain significance	not provided	2023-02-03	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV000568017	SCV000663750	benign	Hereditary cancer-predisposing syndrome	2021-04-13	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000568017	SCV000686335	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-06	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 78 of the RAD51C protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. In a large breast cancer case-control study, this variant was identified in 9/60457 cases and 12/53449 controls - OR=0.663 (95%CI 0.279 to 1.574); p-value=0.387 (PMID: 33471991 - Leiden Open Variation Database DB-ID RAD51C_000098). This variant has been identified in 16/251456 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000236604	SCV002011067	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002487092	SCV002791127	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3; Fanconi anemia complementation group O	2022-03-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003463687	SCV004208008	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2023-05-11	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236604	SCV004220137	uncertain significance	not provided	2022-11-10	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00087 (16/18394 chromosomes in East Asian subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/RAD51C)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354084	SCV001548612	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The RAD51C p.Thr78Ile variant was not identified in the literature nor was it identified in the LOVD 3.0. The variant was identified in dbSNP (ID: rs112832782) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics and Color) . The variant was identified in control databases in 15 of 246228 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the East Asian population in 15 of 17248 chromosomes (freq: 0.0009), while the variant was not observed in the African, Other, Latino, European, Ashkenazi Jewish, Finnish, and South Asian populations. The p.Thr78 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.