Submissions for variant NM_002878.4(RAD51D):c.634G>A (p.Val212Ile)

dbSNP: rs730881948

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160950	SCV000211657	uncertain significance	not provided	2014-07-09	criteria provided, single submitter	clinical testing	This variant is denoted RAD51D c.634G>A at the cDNA level, p.Val212Ile (V212I) at the protein level, and results in the change of a Valine to an Isoleucine (GTT>ATT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD51D Val212Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. RAD51D Val212Ile occurs at a position that is well conserved across species and is not located in a known functional domain (Miller 2014). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether RAD51D Val212Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000565369	SCV000671945	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-15	criteria provided, single submitter	clinical testing	The p.V212I variant (also known as c.634G>A), located in coding exon 7 of the RAD51D gene, results from a G to A substitution at nucleotide position 634. The valine at codon 212 is replaced by isoleucine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 175000 alleles tested) in our clinical cohort. 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.
Color Diagnostics, LLC DBA Color Health	RCV000565369	SCV000908957	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 212 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 not been identified 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	RCV001058835	SCV001223431	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2023-07-16	criteria provided, single submitter	clinical testing	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. 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 RAD51D protein function. ClinVar contains an entry for this variant (Variation ID: 182861). This variant has not been reported in the literature in individuals affected with RAD51D-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 212 of the RAD51D protein (p.Val212Ile).
Baylor Genetics	RCV001058835	SCV005054024	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-01-06	criteria provided, single submitter	clinical testing