Submissions for variant NM_058216.3(RAD51C):c.890T>C (p.Leu297Pro)

gnomAD frequency: 0.00017  dbSNP: rs143026267

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166479	SCV000217277	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-18	criteria provided, single submitter	clinical testing	The p.L297P variant (also known as c.890T>C), located in coding exon 6 of the RAD51C gene, results from a T to C substitution at nucleotide position 890. The leucine at codon 297 is replaced by proline, an amino acid with similar properties. This alteration has been reported in a cohort of 854 patients with apparently sporadic pancreatic cancer (Shindo K et al. J. Clin. Oncol., 2017 Oct;35:3382-3390). This amino acid position is highly 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.
Eurofins Ntd Llc (ga)	RCV000657146	SCV000231811	uncertain significance	not provided	2014-12-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000409000	SCV000489981	uncertain significance	Fanconi anemia complementation group O	2016-09-06	criteria provided, single submitter	clinical testing
Counsyl	RCV000410543	SCV000489982	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2016-09-06	criteria provided, single submitter	clinical testing
Invitae	RCV000409000	SCV000550210	uncertain significance	Fanconi anemia complementation group O	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 297 of the RAD51C protein (p.Leu297Pro). This variant is present in population databases (rs143026267, gnomAD 0.05%). This missense change has been observed in individual(s) with gall bladder adenocarcinoma and an individual undergoing testing for Lynch syndrome (PMID: 25980754, 28767289). ClinVar contains an entry for this variant (Variation ID: 186828). 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 expected to disrupt RAD51C protein function with a positive 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.
GeneDx	RCV000657146	SCV000571427	uncertain significance	not provided	2023-05-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28767289, 34923718, 25980754, 14704354)
Color Diagnostics, LLC DBA Color Health	RCV000166479	SCV000686401	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-12	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with proline at codon 297 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 one individual each affected with triple-negative breast cancer (https://austinpublishinggroup.com/cancer-clinical-research/fulltext/cancer-v5-id1082.pdf), Lynch syndrome-associated cancer and/or polyps (PMID: 25980754) and gallbladder cancer (PMID: 28767289). This variant has been identified in 13/282450 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.
PreventionGenetics, part of Exact Sciences	RCV003891700	SCV000807182	uncertain significance	RAD51C-related condition	2024-01-02	criteria provided, single submitter	clinical testing	The RAD51C c.890T>C variant is predicted to result in the amino acid substitution p.Leu297Pro. This variant has been reported in an individual with non-pancreatic ductal adenocarcinoma of the gallbladder (Table A2, Shindo et al. 2017. PubMed ID: 28767289), an individual with ovarian cancer (Table S1, Boni et al. 2022. PubMed ID: 34923718), and in a patient undergoing genetic testing for Lynch syndrome (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754). This variant is reported in 0.052% of alleles in individuals of African descent in gnomAD and has been interpreted as variant of uncertain significance in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/186828/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657146	SCV001134792	uncertain significance	not provided	2022-08-06	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00052 (13/24946 chromosomes in African/African American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with sporadic pancreatic cancer (PMID: 28767289 (2017)) and history of Lynch syndrome-associated cancer and/or polyps (PMID: 25980754 (2015)). 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.
Genetic Services Laboratory, University of Chicago	RCV001818392	SCV002067017	uncertain significance	not specified	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001818392	SCV002511917	uncertain significance	not specified	2022-04-15	criteria provided, single submitter	clinical testing	Variant summary: RAD51C c.890T>C (p.Leu297Pro) results in a non-conservative amino acid change located in the DNA recombination and repair protein Rad51-like, C-terminal domain (IPR013632) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251048 control chromosomes, predominantly at a frequency of 0.00049 within the African or African-American subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.890T>C has been reported in the literature as a VUS in settings of multigene panel testing of individuals affected with/undergoing testing for Lynch syndrome, apparently sporadic pancreatic cancer (example, Yurgelun_2015, Shindo_2017) and in settings of integrated genomic profiling for patients with cancer (example, Beaubier_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome/RAD51C-related disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000166479	SCV002530029	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-10	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000410543	SCV004019915	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].
Baylor Genetics	RCV000410543	SCV004207925	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2023-10-01	criteria provided, single submitter	clinical testing