Submissions for variant NM_002878.4(RAD51D):c.491T>C (p.Leu164Pro)

gnomAD frequency: 0.00001  dbSNP: rs769287847

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164708	SCV000215376	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-06	criteria provided, single submitter	clinical testing	The p.L164P variant (also known as c.491T>C), located in coding exon 6 of the RAD51D gene, results from a T to C substitution at nucleotide position 491. The leucine at codon 164 is replaced by proline, an amino acid with similar properties. This variant has been observed in individuals affected with breast or ovarian cancer (Song H et al. J Clin Oncol, 2015 Sep;33:2901-7, Tung N et al. J Clin Oncol, 2016 May;34:1460-8, Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000548631	SCV000651752	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-08-01	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 164 of the RAD51D protein (p.Leu164Pro). This variant is present in population databases (rs769287847, gnomAD 0.0009%). This missense change has been observed in individual(s) with ovarian or breast cancer (PMID: 26261251, 26976419, 34326862, 36315097). This variant is also known as c.551T>C (p.Leu184Pro). ClinVar contains an entry for this variant (Variation ID: 185310). 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 RAD51D 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.
Color Diagnostics, LLC DBA Color Health	RCV000164708	SCV000686462	uncertain significance	Hereditary cancer-predisposing syndrome	2021-03-15	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with proline at codon 164 of the RAD51D protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast cancer and ovarian cancer (PMID: 26261251, 26976419). This variant has also been identified in 1/247590 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.
Genetics and Molecular Pathology, SA Pathology	RCV000548631	SCV002761838	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2020-08-11	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358136	SCV001553796	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The RAD51D p.Leu164Pro variant was identified in 2 of 7834 proband chromosomes (frequency: 0.00025) from individuals or families with invasive epithelial ovarian cancer (EOC) and patients with stage I and III breast cancer and was not identified in 5544 control chromosomes from healthy individuals (Song 2015 26261251, Tung 2016 26976419). The variant was also identified in dbSNP (ID: rs769287847) as “With Uncertain significance allele”, ClinVar (3x as uncertain significance by Ambry Genetics, Invitae, Color Genomics) and Clinvitae (2x as uncertain significance). The variant was not identified in Cosmic and Zhejiang University Database. The variant was identified in control databases in 1 of 242382 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European Non-Finnish population in 1 of 109822 chromosomes (freq: 0.000009), while the variant was not observed in the African, “Other”, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The variant was classified in the literature as potentially deleterious rare variant based on in silico analysis (Song 2015 26261251) and as uncertain significance based on ACMG criteria (Tung 2016 26976419). The p.Leu164 residue is conserved across mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the 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.