Submissions for variant NM_058216.3(RAD51C):c.14C>T (p.Thr5Met)

gnomAD frequency: 0.00006  dbSNP: rs201523760

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000590726	SCV000150081	uncertain significance	not provided	2024-04-30	criteria provided, single submitter	clinical testing	Observed in patients with breast cancer, in an individual with clear cell renal cancer, and in unaffected controls, and was absent among affected cases in an ovarian cancer study (PMID: 33471991, 26261251); Published functional studies suggest a neutral effect: homology-directed pair activity similar to wild type (PMID: 37253112); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33471991, 36315097, 26261251, 36243179, 26689913, 37253112)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123370	SCV000166693	uncertain significance	Fanconi anemia complementation group O	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 5 of the RAD51C protein (p.Thr5Met). This variant is present in population databases (rs201523760, gnomAD 0.006%). This missense change has been observed in individual(s) with kidney cancer (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 128203). 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.
Ambry Genetics	RCV000116172	SCV000217272	benign	Hereditary cancer-predisposing syndrome	2024-04-18	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Counsyl	RCV000123370	SCV000489939	uncertain significance	Fanconi anemia complementation group O	2016-08-16	criteria provided, single submitter	clinical testing
Counsyl	RCV000411171	SCV000489940	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2016-08-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116172	SCV000537604	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-27	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with methionine at codon 5 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 been reported in an individual affected with renal clear cell carcinoma (PMID: 26689913) and in an unaffected individual in an ovarian cancer case-control study (PMID: 26261251). This variant has also been identified in 9/251372 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	RCV002307397	SCV000699796	uncertain significance	not specified	2022-10-12	criteria provided, single submitter	clinical testing	Variant summary: RAD51C c.14C>T (p.Thr5Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.8e-05 in 260916 control chromosomes (gnomAD, Song_2015). This frequency is not significantly higher than expected for a pathogenic variant in RAD51C causing Hereditary Breast And Ovarian Cancer Syndrome (3.8e-05 vs 6.3e-05), allowing no conclusion about variant significance. c.14C>T has been reported in the literature in individuals affected kidney renal clear cell carcinoma (Lu_2015) and breast cancer (Dorling_2021), however, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome.The variant was also found in 3 European American women over the age of 70 with no history of cancer (carrier freq=0.0004096, FLOSSIES database), suggesting the variant may be benign. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters have assessed the variant since 2014: all classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590726	SCV001134784	uncertain significance	not provided	2023-07-12	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an individual with kidney cancer (PMID: 26689913 (2015)) as well as in unaffected individuals (PMID: 36243179 (2023), 26261251 (2015)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in an unaffected individual (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/RAD51C)). The frequency of this variant in the general population, 0.000062 (7/113702 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 predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Sema4, Sema4	RCV000116172	SCV002531799	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-17	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002483192	SCV002781099	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3; Fanconi anemia complementation group O	2022-05-26	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000411171	SCV004017734	likely benign	Breast-ovarian cancer, familial, susceptibility to, 3	2023-04-06	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Baylor Genetics	RCV000411171	SCV004209769	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2024-03-27	criteria provided, single submitter	clinical testing