Submissions for variant NM_002878.4(RAD51D):c.29C>T (p.Pro10Leu)

gnomAD frequency: 0.00005  dbSNP: rs759505297

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000550362	SCV000651729	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-11-23	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 10 of the RAD51D protein (p.Pro10Leu). This variant is present in population databases (rs759505297, gnomAD 0.04%). This missense change has been observed in individual(s) with breast and/or ovarian cancer and Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 25980754, 29470806, 34326862). ClinVar contains an entry for this variant (Variation ID: 472596). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Ambry Genetics	RCV000571598	SCV000671929	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-19	criteria provided, single submitter	clinical testing	The p.P10L variant (also known as c.29C>T), located in coding exon 1 of the RAD51D gene, results from a C to T substitution at nucleotide position 29. The proline at codon 10 is replaced by leucine, 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 variant was also identified in a patient with breast and colorectal cancers as part of a large Canadian cohort study of 2870 individuals (Bhai P et al. Front Genet, 2021 Jul;12:698595). 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.
Color Diagnostics, LLC DBA Color Health	RCV000571598	SCV000686442	uncertain significance	Hereditary cancer-predisposing syndrome	2019-03-20	criteria provided, single submitter	clinical testing
GeneDx	RCV001591262	SCV001815011	uncertain significance	not provided	2019-08-22	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in multiple individuals with cancer in published literature, but familial segregation information, in vitro functional studies, and additional clinical information were not included (Yurgelun et al., 2015; Singh et al., 2018); This variant is associated with the following publications: (PMID: 25980754, 29470806)
Baylor Genetics	RCV000550362	SCV004200366	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2023-09-09	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001591262	SCV005623963	uncertain significance	not provided	2023-12-21	criteria provided, single submitter	clinical testing	The RAD51D c.29C>T (p.Pro10Leu) variant has been reported in the published literature in individuals with breast cancer and/or ovarian cancer (PMID: 29470806 (2018)) and a Lynch syndrome associated cancer and/or polyps (PMID: 25980754 (2015)). This variant has also been identified in an individual suspected of hereditary cancer syndrome (PMID: 34326862 (2021)). The frequency of this variant in the general population, 0.00039 (12/30606 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools (i.e., MutationTaster and PolyPhen-2) for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.