Submissions for variant NM_058216.3(RAD51C):c.252G>T (p.Lys84Asn)

gnomAD frequency: 0.00001  dbSNP: rs786202890

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165944	SCV000216700	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-14	criteria provided, single submitter	clinical testing	The p.K84N variant (also known as c.252G>T), located in coding exon 2 of the RAD51C gene, results from a G to T substitution at nucleotide position 252. The lysine at codon 84 is replaced by asparagine, an amino acid with similar properties. One study detected this alteration in 1/3429 patients with invasive epithelial ovarian cancer and 0/2772 control individuals (Song H et al. J. Clin. Oncol., 2015 Sep;33:2901-7). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000195928	SCV000255187	uncertain significance	Fanconi anemia complementation group O	2024-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 84 of the RAD51C protein (p.Lys84Asn). This variant is present in population databases (rs786202890, gnomAD 0.002%). This missense change has been observed in individual(s) with ovarian cancer (PMID: 26261251). ClinVar contains an entry for this variant (Variation ID: 186362). 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.
Color Diagnostics, LLC DBA Color Health	RCV000165944	SCV000912065	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-11	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with asparagine at codon 84 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 an individual affected with ovarian cancer (PMID: 26261251) and in a tumor sample from an individual affected with familial breast cancer (PMID: 35039523). This variant has also been identified in 2/251460 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781943	SCV000920377	uncertain significance	not specified	2017-09-07	criteria provided, single submitter	clinical testing	Variant summary: The RAD51C c.252G>T (p.Lys84Asn) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 126910 control chromosomes. The variant has been reported in one patient with ovarian cancer, without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
GeneDx	RCV001576516	SCV001803722	uncertain significance	not provided	2020-06-16	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with ovarian cancer (Song 2015); This variant is associated with the following publications: (PMID: 26261251)
PreventionGenetics, part of Exact Sciences	RCV003907525	SCV004725230	uncertain significance	RAD51C-related condition	2024-01-05	criteria provided, single submitter	clinical testing	The RAD51C c.252G>T variant is predicted to result in the amino acid substitution p.Lys84Asn. This variant has been reported as a variant of uncertain significance in a patient with ovarian cancer (Song et al. 2015. PubMed ID: 26261251). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, this variant is interpreted as a variant of uncertain significance by multiple laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/186362/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
GenomeConnect - Invitae Patient Insights Network	RCV001535599	SCV001749608	not provided	Breast-ovarian cancer, familial, susceptibility to, 3		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 11-11-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.