Submissions for variant NM_058216.3(RAD51C):c.719T>C (p.Ile240Thr)

gnomAD frequency: 0.00002  dbSNP: rs539341386

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000234057	SCV000291243	uncertain significance	Fanconi anemia complementation group O	2025-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 240 of the RAD51C protein (p.Ile240Thr). This variant is present in population databases (rs539341386, gnomAD 0.009%). This missense change has been observed in individual(s) with breast cancer (PMID: 35264596, 35534704). ClinVar contains an entry for this variant (Variation ID: 241777). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt RAD51C protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect RAD51C function (PMID: 37253112). 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.
Counsyl	RCV000234057	SCV000489903	uncertain significance	Fanconi anemia complementation group O	2016-07-25	criteria provided, single submitter	clinical testing
Counsyl	RCV000409453	SCV000489904	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2016-07-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000573418	SCV000663754	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-26	criteria provided, single submitter	clinical testing	The p.I240T variant (also known as c.719T>C), located in coding exon 5 of the RAD51C gene, results from a T to C substitution at nucleotide position 719. The isoleucine at codon 240 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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	RCV000573418	SCV000686379	uncertain significance	Hereditary cancer-predisposing syndrome	2021-01-25	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 240 of the RAD51C 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 hereditary cancer in the literature. This variant has been identified in 5/251408 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.
Mendelics	RCV000709510	SCV000839334	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
GeneDx	RCV001770208	SCV002002577	uncertain significance	not provided	2023-08-08	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in individual(s) with breast cancer (Guindalini et al., 2022); This variant is associated with the following publications: (PMID: 14704354, 35264596)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001770208	SCV002047222	uncertain significance	not provided	2024-08-14	criteria provided, single submitter	clinical testing	The RAD51C c.719T>C (p.Ile240Thr) variant has been reported in the published literature in individuals affected with breast cancer (PMIDs: 35264596 (2022), 35534704 (2022)). One functional study described the variant as neutral after demonstrating sufficient DNA repair (PMID: 37253112 (2023)). The frequency of this variant in the general population, 0.000087 (3/34592 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.
Fulgent Genetics, Fulgent Genetics	RCV002500818	SCV002776241	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3; Fanconi anemia complementation group O	2022-01-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000409453	SCV004019939	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2023-04-05	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000409453	SCV004209761	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2024-02-17	criteria provided, single submitter	clinical testing