ClinVar Genomic variation as it relates to human health

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

The frequency of this variant in the general population, 0.00026 (9/34592 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 28528518 (2017), 31206626 (2019)) and colorectal cancer (PMID: 30256826 (2018)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/RAD51C)). 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.

This missense variant replaces phenylalanine with leucine at codon 164 of the RAD51C protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast and/or ovarian cancer, and one of them carried a pathogenic BRCA1 variant (PMID: 28528518; Vazquez-Juarez et al, poster P3-07-07, SABCS 2021). In an international breast cancer case-control meta-analysis, this variant was detected in 2/60466 cases and 3/53461 unaffected controls (PMID: 33471991). This variant has been identified in 10/251476 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.

Observed in individuals meeting clinical criteria for Lynch syndrome or hereditary breast and ovarian cancer syndrome, as well as in both cases and controls in breast cancer studies (PMID: 28528518, 33471991, 30256826, 31921681, 31206626, 35534704, 37842866); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30256826, 28528518, 31921681, 31206626, 14704354, 35534704, 33471991, 37842866, Vzquez2021)

Variant summary: RAD51C c.492T>G (p.Phe164Leu) 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 4e-05 in 251476 control chromosomes, predominantly at a frequency of 0.00026 within the Latino subpopulation in the gnomAD database. This frequency is higher than the estimated maximum expected for a pathogenic variant in RAD51C causing Hereditary Breast and Ovarian Cancer Syndrome (6.3e-05), suggesting that the variant might be benign. The variant, c.492T>G, has been reported in the literature in individuals with personal and/or family history of breast and/or ovarian cancer, and other tumor phenotypes (e.g. Cock-Rada_2018, Martin-Morales_2018, Weitzel_2019, Oliver_2019), however it was also found in controls (e.g. Weitzel_2019 and in the FLOSSIES database). In addition, a co-occurrence with another pathogenic variant was reported in one of these individuals (BRCA1 c.1674delA (p.Gly559ValfsX13), Cock-Rada_2018), providing supporting evidence for a benign role. In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 2/60466 cases, but was also found in 3/53461 controls (Dorling_2021, reported through LOVD). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

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].

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 164 of the RAD51C protein (p.Phe164Leu). This variant is present in population databases (rs573992101, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 28528518). ClinVar contains an entry for this variant (Variation ID: 188317). 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.

The p.F164L variant (also known as c.492T>G), located in coding exon 3 of the RAD51C gene, results from a T to G substitution at nucleotide position 492. The phenylalanine at codon 164 is replaced by leucine, an amino acid with highly similar properties. This variant was identified in a cohort of 85 patients undergoing HBOC testing in Colombia (Cock-Rada AM et al. Fam. Cancer, 2018 01;17:23-30). This alteration was also identified in an individual diagnosed with breast cancer (Weitzel JN et al. Cancer, 2019 08;125:2829-2836). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.