Submissions for variant NM_002878.4(RAD51D):c.412A>G (p.Asn138Asp)

dbSNP: rs141690729

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000586154	SCV000211654	uncertain significance	not provided	2024-04-05	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in cases and controls in a breast cancer study (PMID: 33471991); This variant is associated with the following publications: (PMID: 21111057, 14704354, 19327148, 33471991)
Ambry Genetics	RCV000160947	SCV000217873	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-24	criteria provided, single submitter	clinical testing	The p.N138D variant (also known as c.412A>G), located in coding exon 5 of the RAD51D gene, results from an A to G substitution at nucleotide position 412. The asparagine at codon 138 is replaced by aspartic acid, an amino acid with highly similar properties. 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000473960	SCV000551376	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2023-12-15	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 138 of the RAD51D protein (p.Asn138Asp). This variant is present in population databases (rs141690729, gnomAD 0.007%). 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: 182858). 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 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.
Color Diagnostics, LLC DBA Color Health	RCV000160947	SCV000686452	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-04	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with aspartic acid at codon 138 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 ovarian cancer in the literature. In a breast cancer case-control study, this variant has not shown a significant association with disease (PMID: 33471991 - Leiden Open Variation Database DB-ID RAD51D_000147). This variant has been identified in 10/282832 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586154	SCV000698102	uncertain significance	not provided	2017-07-21	criteria provided, single submitter	clinical testing	Variant summary: The RAD51D c.412A>G (p.Asn138Asp) variant located in the DNA recombination and repair protein Rad51-like, C-terminal domain (via InterPro) involves the alteration of a conserved nucleotide and 3/3 in silico tools (SNPsandGO and MutationTaster not captured due to low reliability index and p-value, respectively) predict a benign outcome. However, these predictions have yet to be functionally assessed. This variant was found in 10/277158 control chromosomes at a frequency of 0.0000361, which does not exceed the estimated maximal expected allele frequency of a pathogenic RAD51D variant (0.000125). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586154	SCV001134802	uncertain significance	not provided	2018-12-31	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000160947	SCV002534815	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-23	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267896	SCV002550923	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000473960	SCV002579880	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2022-04-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000473960	SCV004200351	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-03-29	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000473960	SCV005045520	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-05-27	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 138 of the RAD51D protein (p.Asn138Asp). This amino acid position is not well conserved. This variant is present in population databases (rs141690729, gnomAD 0.007%). 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: 182858). In silico analysis supports that this missense variant does not alter protein structure/function. 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.