Submissions for variant NM_058216.3(RAD51C):c.323A>G (p.Asp108Gly)

dbSNP: rs1555593745

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000575198	SCV000663766	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-15	criteria provided, single submitter	clinical testing	The p.D108G variant (also known as c.323A>G), located in coding exon 2 of the RAD51C gene, results from an A to G substitution at nucleotide position 323. The aspartic acid at codon 108 is replaced by glycine, an amino acid with similar properties. In a homology-directed DNA repair (HDR) assay, this alteration showed a functionally abnormal read-out (Hu C et al. Cancer Res, 2023 Aug;83:2557-2571). This alteration was identified in an individual with a personal and/or family history of breast cancer (Pereira JZ et al. Mol Biol Rep, 2022 Oct;49:9509-9520). This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000648237	SCV000770051	uncertain significance	Fanconi anemia complementation group O	2023-05-10	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 expected to disrupt RAD51C protein function. ClinVar contains an entry for this variant (Variation ID: 480494). This variant has not been reported in the literature in individuals affected with RAD51C-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 108 of the RAD51C protein (p.Asp108Gly).
Color Diagnostics, LLC DBA Color Health	RCV000575198	SCV000913137	uncertain significance	Hereditary cancer-predisposing syndrome	2020-09-18	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 108 of the RAD51C protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer 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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV003139870	SCV003807898	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2023-02-10	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4 supporting, PM2 moderated, PP3 supporting
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357413	SCV001552880	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The RAD51C p.Asp108Gly variant was not identified in the literature nor was it identified in the dbSNP, Cosmic, MutDB, or LOVD 3.0 databases. The variant was identified in ClinVar (classified as uncertain significance by Ambry Genetics and Invitae). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Asp108 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.