Submissions for variant NM_058216.3(RAD51C):c.52C>T (p.Pro18Ser)

gnomAD frequency: 0.00004  dbSNP: rs547142453

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000215646	SCV000276747	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-06	criteria provided, single submitter	clinical testing	The p.P18S variant (also known as c.52C>T), located in coding exon 1 of the RAD51C gene, results from a C to T substitution at nucleotide position 52. The proline at codon 18 is replaced by serine, an amino acid with similar properties. This variant was observed in a study of 1010 unrelated Indian patients with breast and/or ovarian cancer (Singh J et al. Breast Cancer Res Treat, 2018 Jul;170:189-196). 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.
GeneDx	RCV000482836	SCV000571571	uncertain significance	not provided	2018-02-05	criteria provided, single submitter	clinical testing	This variant is denoted RAD51C c.52C>T at the cDNA level, p.Pro18Ser (P18S) at the protein level, and results in the change of a Proline to a Serine (CCG>TCG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD51C Pro18Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). RAD51C Pro18Ser is located in the region required for holiday junction resolution activity (UniProt). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether RAD51C Pro18Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000215646	SCV000691243	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-07	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 18 of the RAD51C protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with breast and/or ovarian cancer (PMID: 29470806). This variant has been identified in 10/251454 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000810573	SCV000950786	uncertain significance	Fanconi anemia complementation group O	2023-10-16	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 18 of the RAD51C protein (p.Pro18Ser). This variant is present in population databases (rs547142453, gnomAD 0.03%). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 29470806). ClinVar contains an entry for this variant (Variation ID: 232581). 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. 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.
Baylor Genetics	RCV004567608	SCV005052688	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2024-03-12	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV004567608	SCV005061578	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2024-06-20	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 18 of the RAD51C protein (p.Pro18Ser). TThis amino acid position is well conserved (PhyloP=3.38). This variant is present in population databases (rs547142453, gnomAD 0.03%). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 29470806). ClinVar contains an entry for this variant (Variation ID: 232581). In addition, this alteration is predicted to be tolerated by in silico analysis. 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. Heterozygous pathogenic/likely pathogenic variants in the RAD51C gene are associated with hereditary breast/ovarian cancer (OMIM# 613399).