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

gnomAD frequency: 0.00001  dbSNP: rs779834376

Total submissions: 7

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, 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.
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