Submissions for variant NM_058216.3(RAD51C):c.431T>C (p.Ile144Thr)

gnomAD frequency: 0.00010  dbSNP: rs28363307

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132278	SCV000187362	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-27	criteria provided, single submitter	clinical testing	The p.I144T variant (also known as c.431T>C), located in coding exon 3 of the RAD51C gene, results from a T to C substitution at nucleotide position 431. The isoleucine at codon 144 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in patients with personal and/or family histories of breast and/or ovarian cancer (Loveday C et al. Nat. Genet. 2012 May;44:475-6; author reply 476; Kushnir A et al. Breast Cancer Res. Treat. 2012 Dec;136:869-74; Tung N et al. Cancer. 2015 Jan;121:25-33; Jønson L et al. Breast Cancer Res. Treat. 2016 Jan;155:215-22). However, this alteration was not detected in 3429 patients with invasive epithelial ovarian cancer but was reported in 1 of 2772 controls (Song H et al. J. Clin. Oncol. 2015 Sep;33:2901-7). This alteration was also identified in 1/1358 non-cancer control individuals in a study looking at cancer predisposition mutations in patients with multiple primary cancers (Pritchard AL et al. PLoS ONE 2018 Apr;13(4):e0194098). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000235203	SCV000211631	uncertain significance	not provided	2023-05-03	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate conflicting results with respect to homology-directed repair activity and binding to RAD51C partners (Prakash et al., 2022); This variant is associated with the following publications: (PMID: 23117857, 25318351, 25470109, 26261251, 26740214, 21537932, 29522266, 20052722, 25186627, 30309722, 30924587, 33471991, 35402282, 35039523, 29641532, 36293153, 22538716, 36099300, 14704354)
Invitae	RCV000204997	SCV000259540	uncertain significance	Fanconi anemia complementation group O	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 144 of the RAD51C protein (p.Ile144Thr). This variant is present in population databases (rs28363307, gnomAD 0.02%). This missense change has been observed in individual(s) with ovarian and/or breast cancer (PMID: 21537932, 22538716, 23117857, 25186627, 26261251, 26740214). ClinVar contains an entry for this variant (Variation ID: 142840). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RAD51C protein function with a negative predictive value of 80%. 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.
Counsyl	RCV000204997	SCV000489901	uncertain significance	Fanconi anemia complementation group O	2016-07-22	criteria provided, single submitter	clinical testing
Counsyl	RCV000410651	SCV000489902	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2016-07-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132278	SCV000686352	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 144 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. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 21537932, 22538716, 23117857, 25470109, 26261251, 26740214), ovarian cancer (PMID: 36099300) and endometrial cancer (PMID: 36293153). In a large breast cancer case-control study, this variant has been identified in 11/60466 cases and 16/53461 controls (PMID: 33471991). This variant has also been identified in four women older than age 70 years with no personal history of cancer (FLOSSIES; https://whi.color.com/). This variant has been identified in 16/282878 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.
Eurofins Ntd Llc (ga)	RCV000235203	SCV000859967	uncertain significance	not provided	2018-03-21	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765376	SCV000896642	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3; Fanconi anemia complementation group O	2018-10-31	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000235203	SCV002010672	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235203	SCV002046519	uncertain significance	not provided	2023-06-15	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMID: 25186627 (2015), 25470109 (2015), 26740214 (2016), 36293153 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/RAD51C)), and endometrial cancer (PMID: 36293153 (2022)). This variant is also reported in unaffected individuals (PMID: 26261251 (2015), 29641532 (2018), 36293153 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/RAD51C)). The frequency of this variant in the general population, 0.00024 (6/24968 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002465533	SCV002760968	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000410651	SCV003936815	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2023-07-05	criteria provided, single submitter	clinical testing	This variant previously detected in same tribe. This sequence change replaces isoleucine with threonine at codon 144 of the RAD51C protein (p.Ile144Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs28363307, ExAC 0.01%). This variant has been reported in individuals affected with ovarian and/or breast cancer (PMID: 22538716, 23117857, 26740214, 21537932, 25186627), and in a healthy control individual (PMID: 26261251). ClinVar contains an entry for this variant (Variation ID: 142840). In silico analysis supports that this missense variant has a deleterious effect on protein structure/function based on 9 pathogenic predictions from PolyPhen, DANN, EIGEN, FATHMMMKL, LIST-S2, MutationAssessor, MutationTaster, PrimateAI and SIFT vs 4 benign predictions from BayesDel_addAF, DEOGEN2, M-CAP and MVP. UniProt Variants classifies this variant as Benign, citing 3 articles (25394175, 20301753 and 20301575). Therefore, it has been classified as a Variant of Uncertain Significance.
Myriad Genetics, Inc.	RCV000410651	SCV004019909	likely benign	Breast-ovarian cancer, familial, susceptibility to, 3	2023-04-05	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
PreventionGenetics, part of Exact Sciences	RCV003390825	SCV004120239	uncertain significance	RAD51C-related condition	2023-02-16	criteria provided, single submitter	clinical testing	The RAD51C c.431T>C variant is predicted to result in the amino acid substitution p.Ile144Thr. This variant has been reported in individuals with breast and/or ovarian cancer (Loveday et al. 2012. PubMed ID: 22538716; Jønson et al. 2016. PubMed ID: 26740214; Kushnir A et al 2012. PubMed ID: 23117857; Sopik V et al. 2015. PubMed ID: 25470109; Bu et al. 2022. PubMed ID: 36293153), but has not been reported in association with Fanconi anemia. This variant is reported in 0.0077% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org) and has been interpreted as variant of uncertain significance in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/142840/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV000410651	SCV004209764	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2023-10-19	criteria provided, single submitter	clinical testing
Reproductive Development, Murdoch Childrens Research Institute	RCV000766173	SCV000882507	uncertain significance	Premature ovarian insufficiency	2018-01-10	no assertion criteria provided	research
Leiden Open Variation Database	RCV000235203	SCV001365259	uncertain significance	not provided	2014-11-02	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Christine Rappaport.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354887	SCV001549606	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The RAD51C p.Ile144Thr variant was identified in 5 of 12902 proband chromosomes (frequency: 0.0004) from Danish, Ashkenazi Jewish, and British, individuals or families with HBOC (with or without breast cancer), or BRCA1/2 negative ovarian cancer and was identified in 1 of 7856 control chromosomes (frequency: 0.0001) from healthy individuals (Jonson 2015, Kushnir 2012, Loveday 2012, Song 2015, Yorczyk 2015). The variant was identified in dbSNP (ID: rs28363307) “With Uncertain significance allele”, ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, Invitae, Counsyl, and Color Genomics Inc.), Clinvitae (4x), LOVD 3.0 (1x), and was not identified in Cosmic and MutDB databases. The variant was also identified in control databases in 16 of 277234 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 6 of 24034 chromosomes (freq: 0.0003), and European Non-Finnish in 10 of 126720 chromosomes (freq: 0.00008); it was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Ile144 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Thr variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000235203	SCV001905836	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000235203	SCV001952594	uncertain significance	not provided		no assertion criteria provided	clinical testing