Submissions for variant NM_058216.3(RAD51C):c.523G>A (p.Ala175Thr)

gnomAD frequency: 0.00001  dbSNP: rs587780838

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000123375	SCV000166698	uncertain significance	Fanconi anemia complementation group O	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 175 of the RAD51C protein (p.Ala175Thr). This variant is present in population databases (rs587780838, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer, head and neck squamous cell carcinoma, and/or ovarian cancer (PMID: 21990120, 28678401, 31159747, 34923718, 35264596). ClinVar contains an entry for this variant (Variation ID: 136160). 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 with a positive 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.
GeneDx	RCV000212941	SCV000211634	uncertain significance	not provided	2023-06-22	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal or family history of breast, ovarian, or head and neck cancer (Thompson et al., 2012; Chandrasekharappa et al., 2017; Boni et al., 2021; Guindalini et al., 2022); This variant is associated with the following publications: (PMID: 23117857, 28678401, 34923718, 31159747, 28829762, 25470109, 14704354, 21990120, 35264596)
Ambry Genetics	RCV000160928	SCV000217571	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-08	criteria provided, single submitter	clinical testing	The p.A175T variant (also known as c.523G>A), located in coding exon 3 of the RAD51C gene, results from a G to A substitution at nucleotide position 523. The alanine at codon 175 is replaced by threonine, an amino acid with similar properties. This alteration was previously reported in 1/1053 breast cancer only families and in 0/190 controls (Thompson ER et al. Hum. Mutat. 2012 Jan;33:95-9). This amino acid position is highly 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	RCV000160928	SCV000686360	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-21	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 175 of the RAD51C protein. Computational prediction tool 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 been reported in an individual affected with breast cancer (PMID: 21990120) and in an individual affected with head and neck squamous cell carcinoma (PMID: 28678401). This variant has also been identified in 6/251468 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.
GeneKor MSA	RCV000160928	SCV000822170	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000709504	SCV000839328	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780670	SCV000918129	uncertain significance	not specified	2018-10-05	criteria provided, single submitter	clinical testing	Variant summary: RAD51C c.523G>A (p.Ala175Thr) results in a non-conservative amino acid change located in the ATP-binding domain (IPR020588) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 246252 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.523G>A has been reported in the literature in one individual affected with Breast Cancer (Thompson 2012) and in an individual with head and neck cancer (Chandrasekharappa 2017). These reports do 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. Four 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.
Baylor Genetics	RCV003467097	SCV004209765	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2023-10-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212941	SCV004220146	uncertain significance	not provided	2023-06-22	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMIDs: 31159747 (2019), 25470109 (2015), 21990120 (2012)) and head and neck squamous cell carcinoma (PMID: 28678401 (2017)). The frequency of this variant in the general population, 0.000035 (4/113748 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000780670	SCV004242884	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV000212941	SCV001365264	uncertain significance	not provided	2011-08-25	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Ian Campbell.