ClinVar Miner

Submissions for variant NM_058216.3(RAD51C):c.935G>A (p.Arg312Gln)

gnomAD frequency: 0.00001  dbSNP: rs779834376
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222506 SCV000273254 uncertain significance Hereditary cancer-predisposing syndrome 2022-09-21 criteria provided, single submitter clinical testing The p.R312Q variant (also known as c.935G>A), located in coding exon 7 of the RAD51C gene, results from a G to A substitution at nucleotide position 935. The arginine at codon 312 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in conjunction with another variant in RAD51C in an individual diagnosed with clinical features of Fanconi anemia (Jacquinet A et al. Eur J Med Genet, 2018 May;61:257-261). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics RCV000505229 SCV000598656 uncertain significance Fanconi anemia complementation group O criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000222506 SCV000686406 uncertain significance Hereditary cancer-predisposing syndrome 2022-08-29 criteria provided, single submitter clinical testing This missense variant replaces arginine with glutamine at codon 312 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 having clinical features of Fanconi anemia in compound heterozygosity with a splice site variant c.571+5G>A (PMID: 2927873). In a breast cancer case-control study, this variant has been reported in 1/60466 cases and 1/53461 unaffected controls (OR=0.884; 95%CI 0.055 to 14.136; p-value=1; Leiden Open Variation Database DB-ID RAD51C_000200) (PMID: 33471991). This variant has been identified in 6/251358 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.
Invitae RCV000505229 SCV001558996 likely pathogenic Fanconi anemia complementation group O 2024-01-15 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 312 of the RAD51C protein (p.Arg312Gln). This variant is present in population databases (rs779834376, gnomAD 0.006%). This missense change has been observed in individual(s) with Fanconi anemia (PMID: 29278735). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 229887). 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%. Studies have shown that this missense change is associated with inconclusive levels of altered splicing (Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx RCV001753654 SCV001986388 uncertain significance not provided 2021-06-28 criteria provided, single submitter clinical testing 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: 27535533, 14704354, 29278735)
Sema4, Sema4 RCV000222506 SCV002530034 uncertain significance Hereditary cancer-predisposing syndrome 2022-03-16 criteria provided, single submitter curation
Baylor Genetics RCV002290965 SCV002583277 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 3 no assertion criteria provided clinical testing

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