Submissions for variant NM_058216.3(RAD51C):c.408G>A (p.Met136Ile)

gnomAD frequency: 0.00001  dbSNP: rs587780836

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000123372	SCV000166695	uncertain significance	Fanconi anemia complementation group O	2023-12-25	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 136 of the RAD51C protein (p.Met136Ile). This variant is present in population databases (rs587780836, gnomAD 0.004%). This missense change has been observed in individual(s) with pancreatic cancer (PMID: 28767289). ClinVar contains an entry for this variant (Variation ID: 136158). 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 not expected to disrupt RAD51C protein function with a negative 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.
Ambry Genetics	RCV000215144	SCV000278307	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-15	criteria provided, single submitter	clinical testing	The p.M136I variant (also known as c.408G>A), located in coding exon 3 of the RAD51C gene, results from a G to A substitution at nucleotide position 408. The methionine at codon 136 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been previously reported in an individual with pancreatic ductal adenocarcinoma (Shindo K et al. J. Clin. Oncol., 2017 Oct;35:3382-3390). This amino acid position is not 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.
Color Diagnostics, LLC DBA Color Health	RCV000215144	SCV000906462	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-15	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with isoleucine at codon 136 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 observed in an individual affected with pancreatic cancer (PMID: 28767289) and a healthy control from an ovarian cancer case-control study (PMID: 26261251). This variant has been identified in 3/282870 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.
GeneDx	RCV001582597	SCV001818428	uncertain significance	not provided	2022-07-17	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with pancreatic cancer (Shindo et al., 2017); This variant is associated with the following publications: (PMID: 26261251, 14704354, 28767289, 32659497)
Genetics and Molecular Pathology, SA Pathology	RCV002466441	SCV002761623	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2020-11-06	criteria provided, single submitter	clinical testing	The RAD51C c.408G>A variant is classified as VUS. It is rare and in FLOSSIES, computational analysis equivocal, found in cancer individuals and controls, reported as VUS in ClinVar
PreventionGenetics, part of Exact Sciences	RCV003415929	SCV004115909	uncertain significance	RAD51C-related condition	2023-04-07	criteria provided, single submitter	clinical testing	The RAD51C c.408G>A variant is predicted to result in the amino acid substitution p.Met136Ile. This variant was reported in an individual with pancreatic adenocarcinoma (Table A2, Shindo et al. 2017. PubMed ID: 28767289). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-56774057-G-A) and is reported as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/136158/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.