ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.523G>A (p.Ala175Thr) (rs587780838)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000123375 SCV000166698 uncertain significance Fanconi anemia, complementation group O 2019-11-26 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 175 of the RAD51C protein (p.Ala175Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs587780838, ExAC 0.01%). This variant has been reported in a family affected with breast cancer (PMID: 21990120), and an individual affected with head and neck squamous cell carcinoma (PMID: 28678401). ClinVar contains an entry for this variant (Variation ID: 136160). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx RCV000212941 SCV000211634 uncertain significance not provided 2018-02-11 criteria provided, single submitter clinical testing This variant is denoted RAD51C c.523G>A at the cDNA level, p.Ala175Thr (A175T) at the protein level, and results in the change of an Alanine to a Threonine (GCC>ACC). This variant has been identified in at least one individual with a personal and family history of breast cancer, as well as an individual with head and neck cancer (Thompson 2012, Chandrasekharappa 2017). RAD51C Ala175Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). RAD51C Ala175Thr is located in the region of interaction with RAD51B, RAD51D, and XRCC3 (Miller 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether RAD51C Ala175Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000160928 SCV000217571 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-15 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000160928 SCV000686360 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-11 criteria provided, single submitter clinical testing
GeneKor MSA RCV000160928 SCV000822170 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000709504 SCV000839328 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780670 SCV000918129 uncertain significance not specified 2018-10-05 criteria provided, single submitter clinical testing Variant summary: RAD51C c.523G>A (p.Ala175Thr) 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 2.8e-05 in 246252 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.523G>A has been reported in the literature in one individual affected with Breast Cancer (Thompson 2012) and in an individual with head and neck cancer (Chandrasekharappa 2017). These reports 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. Four 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.
Leiden Open Variation Database RCV000212941 SCV001365264 uncertain significance not provided 2011-08-25 no assertion criteria provided curation Curator: Arleen D. Auerbach. Submitter to LOVD: Ian Campbell.

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