Submissions for variant NM_002878.4(RAD51D):c.752T>A (p.Ile251Lys)

gnomAD frequency: 0.00001  dbSNP: rs778847822

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483141	SCV000565471	uncertain significance	not provided	2023-10-23	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 19327148, 14704354, 21111057)
Color Diagnostics, LLC DBA Color Health	RCV000774916	SCV000908953	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with lysine at codon 251 of the RAD51D 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 not been reported in individuals affected with RAD51D-related disorders in the literature. This variant has been identified in 2/251140 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	RCV001215380	SCV001387120	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 251 of the RAD51D protein (p.Ile251Lys). This variant is present in population databases (rs778847822, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with RAD51D-related conditions. ClinVar contains an entry for this variant (Variation ID: 418446). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt RAD51D 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.
Sema4, Sema4	RCV000774916	SCV002534851	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-06	criteria provided, single submitter	curation
Ambry Genetics	RCV000774916	SCV002669137	uncertain significance	Hereditary cancer-predisposing syndrome	2024-11-03	criteria provided, single submitter	clinical testing	The p.I251K variant (also known as c.752T>A), located in coding exon 9 of the RAD51D gene, results from a T to A substitution at nucleotide position 752. The isoleucine at codon 251 is replaced by lysine, an amino acid with dissimilar properties. This amino acid position is poorly 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.
Baylor Genetics	RCV001215380	SCV004200376	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2023-08-30	criteria provided, single submitter	clinical testing