ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.641G>A (p.Arg214His)

gnomAD frequency: 0.00001  dbSNP: rs760911964
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000574960 SCV000671881 likely benign Hereditary cancer-predisposing syndrome 2016-11-22 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: 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.
Invitae RCV000576239 SCV000677037 uncertain significance Fanconi anemia complementation group O 2023-11-11 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 214 of the RAD51C protein (p.Arg214His). This variant is present in population databases (rs760911964, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of RAD51C-related conditions (PMID: 26057125). ClinVar contains an entry for this variant (Variation ID: 484729). 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.
Color Diagnostics, LLC DBA Color Health RCV000574960 SCV001736446 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-02 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 214 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 ovarian cancer and colon cancer (PMID: 26057125). This variant has been identified in 2/251240 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 RCV001764672 SCV001999222 uncertain significance not provided 2019-10-16 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with a personal or family history including ovarian and colon cancer (Janatova 2015); This variant is associated with the following publications: (PMID: 26057125)
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001354764 SCV001549458 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The RAD51C p.Arg214His variant was identified in 1 of 342 proband chromosomes (frequency: 0.003) from individuals or families with colon cancer and was not identified in 2452 control chromosomes from healthy individuals (Janatova 2015). The variant was also identified in dbSNP (ID: rs760911964 as "With Uncertain significance allele") and ClinVar (1x as likely benign by Ambry Genetics and 1x as uncertain significance by Invitae). The variant was not identified in Cosmic, MutDB, or LOVD 3.0 databases. The variant was identified in control databases in 2 of 246014 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the South Asian population in 2 of 30778 chromosomes (freq: 0.00007), but not in the African, Other, Latino, European, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Arg214 residue is not conserved in mammals and 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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