Submissions for variant NM_002878.4(RAD51D):c.131G>C (p.Gly44Ala)

dbSNP: rs374730714

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000463087	SCV000551326	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-11-12	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 44 of the RAD51D protein (p.Gly44Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ovarian cancer (PMID: 26261251). ClinVar contains an entry for this variant (Variation ID: 410546). 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 tolerated. 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.
GeneDx	RCV000478788	SCV000566457	uncertain significance	not provided	2016-09-21	criteria provided, single submitter	clinical testing	This variant is denoted RAD51D c.131G>C at the cDNA level, p.Gly44Ala (G44A) at the protein level, and results in the change of a Glycine to an Alanine (GGC>GCC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD51D Gly44Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Alanine share similar properties, this is considered a conservative amino acid substitution. RAD51D Gly44Ala occurs at a position that is not conserved and is located in the region that preferentially binds ssDNA (Kim 2011, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether RAD51D Gly44Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000574341	SCV000667158	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-08	criteria provided, single submitter	clinical testing	The p.G44A variant (also known as c.131G>C), located in coding exon 2 of the RAD51D gene, results from a G to C substitution at nucleotide position 131. The glycine at codon 44 is replaced by alanine, an amino acid with similar properties. This alteration was identified in 1/3429 invasive epithelial ovarian cancer patients and in 0/2772 controls which had previously tested negative for mutations in BRCA1/BRCA2 (Song H et al. J. Clin. Oncol. 2015 Sep; 33(26):2901-7). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781804	SCV000920135	uncertain significance	not specified	2018-12-07	criteria provided, single submitter	clinical testing	Variant summary: The variant, RAD51D c.131G>C (p.Gly44Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251812 control chromosomes (gnomAD and Song _2015). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.131G>C, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Song _2015). However, this report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.