Submissions for variant NM_058216.3(RAD51C):c.77A>T (p.Lys26Met)

gnomAD frequency: 0.00003  dbSNP: rs746026526

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000409148	SCV000489961	uncertain significance	Fanconi anemia complementation group O	2016-08-25	criteria provided, single submitter	clinical testing
Counsyl	RCV000410630	SCV000489962	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2016-08-25	criteria provided, single submitter	clinical testing
Invitae	RCV000409148	SCV000550192	uncertain significance	Fanconi anemia complementation group O	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 26 of the RAD51C protein (p.Lys26Met). This variant is present in population databases (rs746026526, gnomAD 0.002%). This missense change has been observed in individual(s) with ovarian cancer and low grade glioma (PMID: 26261251, 26689913). ClinVar contains an entry for this variant (Variation ID: 372089). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RAD51C protein 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.
Ambry Genetics	RCV000566177	SCV000667099	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-15	criteria provided, single submitter	clinical testing	The p.K26M variant (also known as c.77A>T), located in coding exon 1 of the RAD51C gene, results from an A to T substitution at nucleotide position 77. The lysine at codon 26 is replaced by methionine, an amino acid with similar properties. In one study, this alteration was reported in 1/3429 invasive epithelial ovarian cancer and 0/2772 controls (Song H et al. J. Clin. Oncol. 2015 Sep; 33(26):2901-7). This amino acid position is 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780669	SCV000918128	uncertain significance	not specified	2018-09-28	criteria provided, single submitter	clinical testing	Variant summary: RAD51C c.77A>T (p.Lys26Met) results in a non-conservative amino acid change in 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 1.1e-05 in 282776 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.77A>T has been reported in the literature in individuals affected with Ovarian Cancer or glioma. These report(s) 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. Three 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.
Color Diagnostics, LLC DBA Color Health	RCV000566177	SCV001348037	uncertain significance	Hereditary cancer-predisposing syndrome	2018-11-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000566177	SCV002530014	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-31	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000410630	SCV004019965	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.